Indole carboxamide compounds

ABSTRACT

or a salt thereof, wherein: X is CR4 or N; R1, R2, R3, R4, and A are defined herein. Also disclosed are methods of using such compounds as inhibitors of Bruton&#39;s tyrosine kinase (Btk), and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This continuation application claims the priority benefit of U.S. patentapplication Ser. No. 14/921,347 filed Oct. 23, 2015, which claims thebenefit of U.S. Application Ser. No. 62/068,225, filed Oct. 24, 2014,which is incorporated herein it its entirety.

The present invention generally relates to indole carboxamide compoundsuseful as kinase inhibitors, including the modulation of Bruton'styrosine kinase (Btk) and other Tec family kinases such as Itk. Providedherein are indole carboxamide compounds, compositions comprising suchcompounds, and methods of their use. The invention further pertains topharmaceutical compositions containing at least one compound accordingto the invention that are useful for the treatment of conditions relatedto kinase modulation and methods of inhibiting the activity of kinases,including Btk and other Tec family kinases such as Itk, in a mammal.

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Btk is a member of the Tec family of tyrosinekinases, and is a regulator of early B-cell development, as well asmature B-cell activation, signaling, and survival.

B-cell signaling through the B-cell receptor (BCR) leads to a wide rangeof biological outputs, which in turn depend on the developmental stageof the B-cell. The magnitude and duration of BCR signals must beprecisely regulated. Aberrant BCR-mediated signaling can causedisregulated B-cell activation and/or the formation of pathogenicauto-antibodies leading to multiple autoimmune and/or inflammatorydiseases. Mutation of Btk in humans results in X-linkedagammaglobulinaemia (XLA). This disease is associated with the impairedmaturation of B-cells, diminished immunoglobulin production, compromisedT-cell-independent immune responses and marked attenuation of thesustained calcium signal upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmunedisease and/or inflammatory disease has been established inBtk-deficient mouse models. For example, in standard murine preclinicalmodels of systemic lupus erythematosus (SLE), Btk deficiency has beenshown to result in a marked amelioration of disease progression.Moreover, Btk deficient mice are also resistant to developingcollagen-induced arthritis and are less susceptible toStaphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoralimmune system in the pathogenesis of autoimmune and/or inflammatorydiseases. Protein-based therapeutics such as rituximab, developed todeplete B-cells, represent an important approach to the treatment of anumber of autoimmune and/or inflammatory diseases. Because of Btk's rolein B-cell activation, inhibitors of Btk can be useful as inhibitors ofB-cell mediated pathogenic activity (such as autoantibody production).

Btk is also expressed in mast cells and monocytes and has been shown tobe important for the function of these cells. For example, Btkdeficiency in mice is associated with impaired IgE-mediated mast cellactivation (marked diminution of TNF-alpha and other inflammatorycytokine release), and Btk deficiency in humans is associated withgreatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment ofallergic disorders and/or autoimmune and/or inflammatory diseasesincluding, but not limited to: SLE, rheumatoid arthritis, multiplevasculitides, idiopathic thrombocytopenic purpura (ITP), myastheniagravis, allergic rhinitis, multiple sclerosis (MS), transplantrejection, type I diabetes, membranous nephritis, inflammatory boweldisease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold andwarm agglutinin diseases, Evans syndrome, hemolytic uremicsyndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis,Sjögren's syndrome, peripheral neuropathies (e.g., Guillain-Barresyndrome), pemphigus vulgaris, and asthma.

In addition, Btk has been reported to play a role in controlling B-cellsurvival in certain B-cell cancers. For example, Btk has been shown tobe important for the survival of BCR-Abl-positive B-cell acutelymphoblastic leukemia cells. Thus inhibition of Btk activity can beuseful for the treatment of B-cell lymphoma and leukemia.

In view of the numerous conditions that are contemplated to benefit bytreatment involving modulation of protein kinases, it is immediatelyapparent that new compounds capable of modulating protein kinases suchas Btk and methods of using these compounds should provide substantialtherapeutic benefits to a wide variety of patients.

U.S. Pat. Nos. 8,084,620 and 8,685,969 disclose tricyclic carboxamidecompounds useful as kinase inhibitors, including the modulation of Btkand other Tec family kinases.

There still remains a need for compounds useful as Btk inhibitors.Applicants have found potent compounds that have activity as Btkinhibitors. These compounds are provided to be useful as pharmaceuticalswith desirable stability, bioavailability, therapeutic index, andtoxicity values that are important to this utility.

SUMMARY OF THE INVENTION

The present invention provides indole carboxamide compounds, includingsalts, solvates, and prodrugs thereof, that are useful as inhibitors ofBtk and are useful for the treatment of proliferative diseases, allergicdiseases, autoimmune diseases and inflammatory diseases.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of Formula (I) or salts, solvates, and prodrugs thereof.

The present invention also provides a method of inhibiting Btk activitycomprising administering to a mammal in need thereof at least one of thecompounds of Formula (I) or salts, solvates, and prodrugs thereof.

The present invention also provides a method for treating allergicdisorders and/or autoimmune and/or inflammatory diseases, comprisingadministering to a mammal in need thereof at least one of the compoundsof Formula (I) or salts, solvates, and prodrugs thereof.

The present invention also provides a method for treating proliferativediseases, such as cancer, comprising administering to a mammal in needthereof at least one of the compounds of Formula (I) or salts, solvates,and prodrugs thereof.

The present invention also provides a method of treating a disease ordisorder associated with Btk activity, the method comprisingadministering to a mammal in need thereof, at least one of the compoundsof Formula (I) or salts, solvates, and prodrugs thereof.

The present invention also provides processes and intermediates formaking the compounds of Formula (I) including salts, solvates, andprodrugs thereof.

The present invention also provides at least one of the compounds ofFormula (I) or salts, solvates, and prodrugs thereof, for use intherapy.

The present invention also provides the use of at least one of thecompounds of Formula (I) or salts, solvates, and prodrugs thereof, forthe manufacture of a medicament for the treatment or prophylaxis of Btkrelated conditions, such as proliferative diseases, allergic diseases,autoimmune diseases and inflammatory diseases.

The present invention also provides the use of at least one of thecompounds of Formula (I) or salts, solvates, and prodrugs thereof, forthe manufacture of a medicament for treatment of cancer.

The compounds of Formula (I) and compositions comprising the compoundsof Formula (I) may be used in treating, preventing, or curing variousBtk related conditions. Pharmaceutical compositions comprising thesecompounds are useful in treating, preventing, or slowing the progressionof diseases or disorders in a variety of therapeutic areas, such asproliferative diseases, allergic diseases, autoimmune diseases andinflammatory diseases.

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION

The first aspect of the present invention provides at least one compoundof Formula (I):

-   or a salt thereof, wherein:-   X is CR₄ or N;-   A is:

or

-   -   (vi) —CHR₈(pyridinyl) wherein each pyridinyl is substituted with        R₆ and R₉;

-   Q₁ is —NR₇Q₂, —CR₁₀R₁₀NR₇Q₂, —C(O)NR₇(C₁₋₄ alkyl substituted with    zero or 1 R₁₁), —CH═CH₂, —CH═C(CN)S(O)₂CH₃, —S(O)₂CH═CR₁₀R₁₀,    —NR₇(dichlorotriazinyl), —NR₇(quinazolin-4-yl substituted with zero    or 1 R₁₁), 3-methylenepyrrolidin-2-on-1-yl, or a cyclic group    selected from 1H-pyrrol-2(5H)-on-1-yl, isoindolin-1-on-2-yl,    quinazolin-4(3H)-on-3-yl, and quinazoline-2,4(1H, 3H)-dion-3-yl,    each cyclic group substituted with zero to two substituents    independently selected from F, Cl, —CH₃, —CN, and —OCH₃;

-   Q₂ is —CN, —C(O)(C₁₋₄ alkyl substituted with zero or 1 R₁₁),    —C(O)(C₃₋₆ cycloalkyl substituted with zero or 1 R₁₁), —C(O)(C₅₋₆    cycloalkenyl), —C(O)CR₁₀═CR₁₀R₁₀, —C(O)C(R₁₀)═CHCH₂N(CH₃)₂,    —C(O)C≡CR₇, —C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡C(phenyl),    —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CHR₁₀;

-   R₁ is H, —CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂;

-   R₂ is H, —CH₃, cyclopropyl, or phenyl substituted with zero or 1    R₁₂, provided that zero or one of R₁ and R₂ is phenyl substituted    with zero or 1 R₁₂;

-   R₃ is H, F, Cl, I, —CN, or —CH₃;

-   R₄ is H, F, —OH, —O(C₁₋₄ alkyl), —O(C₁₋₄ alkyl)-O—(C₁₋₂ alkyl),    —O(CH₂)₁₋₃(phenyl), —O(CH₂)₁₋₃(methoxyphenyl), or    —O(CH₂)₁₋₃(morpholinyl);

-   R₅ is H, F, Cl, or —CH₃;

-   R₆ is H, F, Cl, —CF₃, or C₁₋₃ alkoxy;

-   each R_(6a) is independently H or F;

-   R₇, at each occurrence, is independently H, C₁₋₄ alkyl, or    cyclopropyl;

-   R₈ is H or C₁₋₄ alkyl;

-   R₉ is —CH═CH₂, —CH═CHCH₂N(CH₃)₂, —C≡CH, or —C≡CCH₃;

-   R₁₀, at each occurrence, is independently H or —CH₃;

-   R₁₁ is F, Cl, —CN, —CF₃, or C₁₋₃ alkoxy; and

-   R₁₂ is F, Cl, —CN, —CF₃, or C₁₋₃ alkoxy.

The second aspect of the present invention provides at least onecompound of Formula (I) in which X is CR₄, having the structure ofFormula (Ia):

-   or a salt thereof, wherein:-   A is:

or

-   -   (vi) —CHR₈(pyridinyl) wherein each pyridinyl is substituted with        R₆ and R₉;

-   Q₁ is —NR₇Q₂, —CR₁₀R₁₀NR₇Q₂, —C(O)NR₇(C₁₋₄ alkyl substituted with    zero or 1 R₁₁), —CH═C(CN)S(O)₂CH₃, —S(O)₂CH═CR₁₀R₁₀,    —NR₇(dichlorotriazinyl), —NR₇(quinazolin-4-yl substituted with zero    or 1 R₁₁), 3-methylenepyrrolidin-2-on-1-yl, or a cyclic group    selected from 1H-pyrrol-2(5H)-on-1-yl, isoindolin-1-on-2-yl,    quinazolin-4(3H)-on-3-yl, and quinazoline-2,4(1H, 3H)-dion-3-yl,    each cyclic group substituted with zero to two substituents    independently selected from F, Cl, —CH₃, —CN, and —OCH₃;

-   Q₂ is —CN, —C(O)(C₁₋₄ alkyl substituted with zero or 1 R₁₁),    —C(O)(C₃₋₆ cycloalkyl substituted with zero or 1 R₁₁), —C(O)(C₅₋₆    cycloalkenyl), —C(O)CR₁₀═CR₁₀R₁₀, —C(O)C(R₁₀)═CHCH₂N(CH₃)₂,    —C(O)C≡CR₇, —C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡C(phenyl),    —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CHR₁₀;

-   R₁ is H, —CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂;

-   R₂ is H, —CH₃, cyclopropyl, or phenyl substituted with zero or 1    R₁₂;

-   provided that zero or one of R₁ and R₂ is phenyl substituted with    zero or 1 R₁₂;

-   R₃ is H, F, Cl, —CH₃, or —CN;

-   R₄ is H, F, —OH, —O(C₁₋₄ alkyl), —O(C₁₋₄ alkyl)-O—(C₁₋₂ alkyl),    —O(CH₂)₁₃(phenyl), —O(CH₂)₁₋₃(methoxyphenyl), or    —O(CH₂)₁₋₃(morpholinyl);

-   R₅ is H, F, Cl, or —CH₃;

-   R₆ is H, F, Cl, —CF₃, or C₁₋₃ alkoxy;

-   R₇, at each occurrence, is independently H, C₁₋₄ alkyl, or    cyclopropyl;

-   R₈ is H or C₁₋₄ alkyl;

-   R₉ is —CH═CH₂, —CH═CHCH₂N(CH₃)₂, —C≡CH, or —C≡CCH₃;

-   R₁₀, at each occurrence, is independently H or —CH₃;

-   R₁₁ is F, Cl, —CN, —CF₃, or C₁₋₃ alkoxy; and

-   R₁₂ is F, Cl, —CN, —CF₃, or C₁₋₃ alkoxy.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein: X is CR₄; and R₁, R₂, R₃, R₄, and A are defined in the firstaspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein: X is N; and R₁, R₂, R₃, and A are defined in the first aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein: Q₁ is —NR₇Q₂, —CR₁₀R₁₀NR₇Q₂, —C(O)NR₇(C₁₋₄ alkyl substitutedwith zero or 1 R₁₁), —CH═CH₂, —CH═C(CN)S(O)₂CH₃, —S(O)₂CH═CR₁₀R₁₀,—NR₇(dichlorotriazinyl), —NR₇(quinazolin-4-yl substituted with zero or 1R₁₁), 3-methylenepyrrolidin-2-on-1-yl, or a cyclic group selected from1H-pyrrol-2(5H)-on-1-yl, isoindolin-1-on-2-yl, quinazolin-4(3H)-on-3-yl,and quinazoline-2,4(1H, 3H)-dion-3-yl, each cyclic group substitutedwith zero to two substituents independently selected from F, Cl, —CH₃,—CN, and —OCH₃.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein: Q₁ is —NR₇Q₂, —CR₁₀R₁₀NR₇Q₂, —S(O)₂CH═CR₁₀R₁₀,—NR₇(dichlorotriazinyl), 1H-pyrrol-2(5H)-on-1-yl, or3-methylenepyrrolidin-2-on-1-yl; Q₂ is —CN, —C(O)(C₅₋₆ cycloalkenyl),—C(O)CH═CHR₁₀, —C(O)CR₁₀═CH₂, —C(O)CR₁₀═CHCH₂N(CH₃)₂, —C(O)C≡CR₇,—C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡C(phenyl), —C(O)C≡CSi(CH₃)₃, or—S(O)₂CH═CH₂; R₃ is H, F, or Cl; R₄, when present, is H or F; and X, R₁,R₂, R₅, R₆, R₇, R₈, R₉, R₁₀, and A are defined in either the firstaspect or the second aspect. Included in this embodiment are compoundsin which X is CR₄.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein: Q₁ is —NR₇Q₂ or —S(O)₂CH═CH₂; Q₂ is —C(O)CH═CH₂,—C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl), —C(O)C≡C(C₁₋₃hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₃ is H, F, or Cl; R₄,when present, is H or F; and X, R₁, R₂, R₅, R₆, R₇, R₈, R₉, R₁₀, and Aare defined in either the first aspect or the second aspect. Included inthis embodiment are compounds in which X is CR₄.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A

Q₁ is —NR₇Q₂ or —S(O)₂CH═CH₂; Q₂ is —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂,—C(O)C≡CR₇, —C(O)C≡C(phenyl), —C(O)C≡C(C₁₋₃ hydroxyalkyl),—C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H, —CH₃, —CF₃, or phenylsubstituted with zero or 1 R₁₂; and R₂ is H, —CH₃, cyclopropyl, orphenyl substituted with zero or 1 R₁₂; provided that zero or one of R₁and R₂ is phenyl substituted with zero or 1 R₁₂ and further providedthat at least one of R₁ and R₂ is —CH₃; R₃ is H, F, or Cl; R₄, whenpresent, is H or F; R₅ is H, —CH₃, F or Cl; R₆ is H, F, Cl, —CF₃ or C₁₋₃alkoxy; and R₇ and R₁₂ are defined in either the first aspect or thesecond aspect. Included in this embodiment are compounds in which X isCR₄.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₁ is —CH═CH₂, —NR₇Q₂, or —S(O)₂CH═CH₂; Q₂ is —C(O)CH═CH₂,—C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl), —C(O)C≡C(C₁₋₃hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H, —CH₃, —CF₃,or phenyl substituted with zero or 1 R₁₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄, when present, is H or F; R₅ is H, —CH₃, F or Cl; R₆ is H, F, Cl,—CF₃ or C₁₋₃ alkoxy; and R₇ and R₁₂ are defined in either the firstaspect or the second aspect. Included in this embodiment are compoundsin which X is CR₄.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₂ is —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl),—C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H,—CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄, when present, is H or F; R₆ is H, F, Cl, —CF₃ or C₁₋₃ alkoxy;and R₇ and R₁₂ are defined in either the first aspect or the secondaspect. Included in this embodiment are compounds in which X is CR₄.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₁ is —CH═CH₂, —NR₇Q₂, or —S(O)₂CH═CH₂; Q₂ is —C(O)CH═CH₂,—C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl), —C(O)C≡C(C₁₋₃hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; Q₂ is —C(O)CH═CH₂,—C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl), —C(O)C≡C(C₁₋₃hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H, —CH₃, —CF₃,or phenyl substituted with zero or 1 R₁₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄ is H or F; R₆ is H, F, Cl, —CF₃ or C₁₋₃ alkoxy; R_(6a) is definedin the first aspect; and R₇ and R₁₂ are defined in either the firstaspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₂ is —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl),—C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H,—CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄ is H or F; R₆ is H, F, Cl, —CF₃ or C₁₋₃ alkoxy; and R₇ and R₁₂are defined in either the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₂ is —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl),—C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H,—CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄ is H or F; each R₇ is independently H, C₁₋₄ alkyl, orcyclopropyl; and R₁₂ is defined in either the first aspect or the secondaspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₂ is —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl),—C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H,—CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄ is H or F; each R₇ is independently H, C₁₋₄ alkyl, orcyclopropyl; and R₁₂ is defined in either the first aspect or the secondaspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₂ is —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl),—C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H,—CH₃, —CF₃, or phenyl substituted with zero or 1 R₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄ is H or F; and R₇ and R₁₂ are defined in either the first aspector the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₂ is —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl),—C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H,—CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄ is H or F; and R₇ and R₁₂ are defined in either the first aspector the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₂ is —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl),—C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H,—CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄ is H or F; and R₇ and R₂ are defined in either the first aspector the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₂ is —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl),—C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H,—CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄ is H or F; and R₇ and R₁₂ are defined in either the first aspector the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

Q₂ is —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(phenyl),—C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CH₂; R₁ is H,—CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂; and R₂ is H, —CH₃,cyclopropyl, or phenyl substituted with zero or 1 R₁₂; provided thatzero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂ andfurther provided that at least one of R₁ and R₂ is —CH₃; R₃ is H, F, orCl; R₄ is H or F; each R₇ is independently C₁₋₄ alkyl or cyclopropyl;and R₁₂ is defined in either the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is —CHR₈(pyridinyl) wherein each pyridinyl is substituted withR₆ and R₉; R₁ is H, —CH₃, —CF₃, or phenyl substituted with zero or 1R₁₂; and R₂ is H, —CH₃, cyclopropyl, or phenyl substituted with zero or1 R₁₂; provided that zero or one of R₁ and R₂ is phenyl substituted withzero or 1 R₁₂ and further provided that at least one of R₁ and R₂ is—CH₃; R₃ is H, F, or Cl; R₄ is H or F; R₆ is H; R₈ is H or C₁₋₄ alkyl;R₉ is —CH═CH₂, —CH═CHCH₂N(CH₃)₂, —C≡CH, or —C≡CCH₃; and R₁₂ is definedin either the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is H, —CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂;and R₂ is H, —CH₃, cyclopropyl, or phenyl substituted with zero or 1R₁₂; provided that zero or one of R₁ and R₂ is phenyl substituted withzero or 1 R₁₂ and further provided that at least one of R₁ and R₂ is—CH₃; and R₃, R₄, R₁₂ and A are defined in either the first aspect orthe second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is H, —CF₃ or —CH₃; and R₂ is H or —CH₃: provided that one ofR₁ and R₂ is —CH₃ or —CF₃ and the other of R₁ and R₂ is H; and R₃, R₄,and A are defined in either the first aspect or the second aspect.Included in this embodiment are compounds in which R₁ is —CH₃ and R₂ isH. Also included in this embodiment are compounds in which R₁ is H andR₂ is —CH₃.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is —CH₃; R₂ is —CH₃; and R₃, R₄, and A are defined in eitherthe first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is —CF₃; R₂ is —CH₃; and R₃, R₄, and A are defined in eitherthe first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is —CH₃; R₂ is cyclopropyl; and R₃, R₄, and A are defined ineither the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is 4-fluorophenyl; R₂ is —CH₃; and R₃, R₄, and A are definedin either the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is —CH₃; R₂ is 4-fluorophenyl; and R₃, R₄, and A are definedin either the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₃ is H, F, Cl, I, —CN, or —CH₃; and R₁, R₂, R₄, and A aredefined in either the first aspect or the second aspect. Included inthis embodiment are compounds in which R₃ is H or F. Also included inthis embodiment are compounds in which R₁ is H, —CH₃, —CF₃, or phenylsubstituted with zero or 1 R₁₂; and R₂ is H, —CH₃, cyclopropyl, orphenyl substituted with zero or 1 R₁₂; provided that zero or one of R₁and R₂ is phenyl substituted with zero or 1 R₁₂ and further providedthat at least one of R₁ and R₂ is —CH₃.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₃ is H, F, or Cl; and R₁, R₂, R₄, and A are defined in eitherthe first aspect or the second aspect. Included in this embodiment arecompounds in which R₃ is H or F. Also included in this embodiment arecompounds in which R₁ is H, —CH₃, —CF₃, or phenyl substituted with zeroor 1 R₁₂; and R₂ is H, —CH₃, cyclopropyl, or phenyl substituted withzero or 1 R₁₂; provided that zero or one of R₁ and R₂ is phenylsubstituted with zero or 1 R₁₂ and further provided that at least one ofR₁ and R₂ is —CH₃.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₃ is F, Cl, or I; and R₁, R₂, R₄, and A are defined in eitherthe first aspect or the second aspect. Included in this embodiment arecompounds in which R₃ is F or CL. Also included in this embodiment arecompounds in which R₃ is F.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₄ is H, F, —OH, —O(C₁₋₂ alkyl), —OCH₂CH₂OCH₃, —OCH₂(phenyl),—OCH₂(methoxyphenyl), or —OCH₂(morpholinyl); and R₁, R₂, R₃, and A aredefined in either the first aspect or the second aspect. Included inthis embodiment are compounds in which R₄ is H or F. Also included inthis embodiment are compounds in which R₁ is H, —CH₃, —CF₃, or phenylsubstituted with zero or 1 R₁₂; and R₂ is H, —CH₃, cyclopropyl, orphenyl substituted with zero or 1 R₁₂; provided that zero or one of R₁and R₂ is phenyl substituted with zero or 1 R₁₂ and further providedthat at least one of R₁ and R₂ is —CH₃; and R₃ is H or F.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is

R₅ is H, F, or —CH₃; and R₁, R₂, R₃, R₄, and R₆ are defined in eitherthe first aspect or the second aspect. Included in this embodiment arecompounds in which R₆ is H. Also included in this embodiment arecompounds in which R₁ is H, —CH₃, —CF₃, or phenyl substituted with zeroor 1 R₁₂; and R₂ is H, —CH₃, cyclopropyl, or phenyl substituted withzero or 1 R₁₂; provided that zero or one of R₁ and R₂ is phenylsubstituted with zero or 1 R₁₂ and further provided that at least one ofR₁ and R₂ is —CH₃; R₃ is H or F; R₄ is H or F; R₆ is H; and R₁₂ isdefined in either the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₆ is H or F; and R₁, R₂, R₃, R₄, R₅, and A are defined ineither the first aspect or the second aspect. Included in thisembodiment are compounds in which R₆ is H. Also included are compoundsin which R₁ is H, —CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂;and R₂ is H, —CH₃, cyclopropyl, or phenyl substituted with zero or 1R₁₂; provided that zero or one of R₁ and R₂ is phenyl substituted withzero or 1 R₁₂ and further provided that at least one of R₁ and R₂ is—CH₃; R₃ is H or F; R₄ is H or F; R₅ is H, F, or —CH₃; R₆ is H or F; andR₁₂ is defined in either the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₇, at each occurrence, is independently H or C₁₋₂ alkyl; andR₁, R₂, R₃, R₄, and A are defined in either the first aspect or thesecond aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is —CHR₈(pyridinyl) wherein each pyridinyl is substituted withR₆ and R₉; R₈ is H or —CH₃; and R₁, R₂, R₃, R₄, R₆, and R₉ are definedin either the first aspect or the second aspect. Included in thisembodiment are compounds in which R₁ is H, —CH₃, —CF₃, or phenylsubstituted with zero or 1 R₁₂; and R₂ is H, —CH₃, cyclopropyl, orphenyl substituted with zero or 1 R₁₂; provided that zero or one of R₁and R₂ is phenyl substituted with zero or 1 R₁₂ and further providedthat at least one of R₁ and R₂ is —CH₃; R₃ is H or F; R₄ is H or F; R₅is H, F, or —CH₃; R₆ is H; R₉ is —CH═CH₂ or —C≡CCH₃; and R₁₂ is definedin either the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is —CHR₈(pyridinyl) wherein each pyridinyl is substituted withR₆ and R₉; R₉ is —CH═CH₂, —C≡CH, or —C≡CCH₃; and R₁, R₂, R₃, R₄, R₆, andR₈ are defined in either the first aspect or the second aspect. Includedin this embodiment are compounds in which R₉ is —CH═CH₂ or —C≡CCH₃.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is F, Cl, —CN, —CF₃, or C₁₋₃ alkoxy; and R₁, R₂, R₃, R₄, andA are defined in either the first aspect or the second aspect. Includedin this embodiment are compounds in which Rn is F or —CN.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is H, —CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂;and R₂ is H, —CH₃, cyclopropyl, or phenyl substituted with zero or 1R₁₂; provided that zero or one of R₁ and R₂ is phenyl substituted withzero or 1 R₁₂ and further provided that at least one of R₁ and R₂ is—CH₃; R₃ is H, F, or Cl; R₄ is H, F, —OH, —O(C₁₋₂ alkyl), —OCH₂CH₂OCH₃,—OCH₂(phenyl), —OCH₂(methoxyphenyl), or —OCH₂CH₂(morpholinyl); R₅ is H,F, or —CH₃; R₆ is H or F; R₇ is H or C₁₋₃ alkyl; R₈ is H or —CH₃; R₉ is—CH═CH₂ or —C≡CCH₃; Q₁ is —N(CH₃)C(O)CH═CH₂, —N(CH₃)S(O)₂CH═CH₂,—C(O)NHCH₂CN, —C(CH₃)₂NHS(O)₂CH═CH₂, —CH₂NHC(O)CH═CH₂,—CH₂NHS(O)₂CH═CH₂, —NHC(O)CH₂CN, —NHC(O)CH₂CH₃, —NHC(O)CH═CH₂,—NHC(O)C(CH₃)═CH₂, —NHC(O)CH═C(CH₃)₂, —NHC(O)CH═CHCH₃,—NHC(O)CH═CHCH₂N(CH₃)₂, —NHC(O)(cyclohexenyl), —NHC(O)(cyclopropyl),—NHC(O)(cyanocyclopropyl), —NHS(O)₂CH═CH₂, —S(O)₂CH═CH₂,—CH═C(CN)S(O)₂CH₃, —NH(dichlorotriazinyl), —NH(fluoroquinazolin-4-yl),3-methylenepyrrolidin-2-on-1-yl, or a cyclic group selected from1H-pyrrol-2(5H)-on-1-yl, isoindolin-1-on-2-yl, quinazolin-4(3H)-on-3-yl,and quinazoline-2,4(1H, 3H)-dion-3-yl, each cyclic group substitutedwith zero to two substituents independently selected from F, Cl, —CH₃,—CN, and —OCH₃; Q₂ is —CN, —C(O)CH═CH₂, —S(O)₂CH═CH₂,—C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CH, —C(O)C≡CCH₃, —C(O)C≡CCH₂CH₃,—C(O)C≡CCH₂CH₂CH₃, —C(O)C≡C(CH₃)₂OH, —C(O)C≡CSi(CH₃)₃,—C(O)C≡C(cyclopropyl), or —C(O)C≡C(phenyl); and A and R₁₂ are defined ineither the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

R₁ is H, —CH₃, —CF₃, or 4-fluorophenyl; and R₂ is H, —CH₃, cyclopropyl,or 4-fluorophenyl; provided that zero or one of R₁ and R₂ is4-fluorophenyl and further provided that at least one of R₁ and R₂ is—CH₃; R₃ is H, F, or Cl; R₄ is H, F, —OH, —O(C₁₋₂ alkyl), —OCH₂CH₂OCH₃,—OCH₂(phenyl), or —OCH₂(morpholinyl); R₅ is H, F, or —CH₃; R₆ is H; andQ₁ is —N(CH₃)C(O)CH═CH₂, —N(CH₃)S(O)₂CH═CH₂, —C(O)NHCH₂CN,—C(CH₃)₂NHS(O)₂CH═CH₂, —CH₂NHC(O)CH═CH₂, —CH₂NHS(O)₂CH═CH₂,—NHC(O)CH₂CN, —NHC(O)CH₂CH₃, —NHC(O)CH═CH₂, —NHC(O)C(CH₃)═CH₂,—NHC(O)CH═C(CH₃)₂, —NHC(O)CH═CHCH₃, —NHC(O)CH═CHCH₂N(CH₃)₂,—NHC(O)(cyclohexenyl), —NHC(O)(cyclopropyl), —NHC(O)(cyanocyclopropyl),—NHS(O)₂CH═CH₂, —S(O)₂CH═CH₂, —CH═C(CN)S(O)₂CH₃, —NH(dichlorotriazinyl),—NH(fluoroquinazolin-4-yl), 3-methylenepyrrolidin-2-on-1-yl, or a cyclicgroup selected from 1H-pyrrol-2(5H)-on-1-yl, isoindolin-1-on-2-yl,quinazolin-4(3H)-on-3-yl, and quinazoline-2,4(1H, 3H)-dion-3-yl, eachcyclic group substituted with zero to two substituents independentlyselected from F, Cl, —CH₃, —CN, and —OCH₃. Included in this embodimentare compounds in which A is

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

R₁ is H, —CH₃, —CF₃, or 4-fluorophenyl; and R₂ is H, —CH₃, cyclopropyl,or 4-fluorophenyl; provided that zero or one of R₁ and R₂ is4-fluorophenyl and further provided that at least one of R₁ and R₂ is—CH₃; R₃ is H or F; R₄ is H or F; R₆ is H or F; and Q₂ is —CN,—C(O)CH═CH₂, —C(O)C≡CCH₃, or —S(O)₂CH═CH₂. Included in this embodimentare compounds in which R₃ is F.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

R₁ is H, —CH₃, —CF₃, or 4-fluorophenyl; and R₂ is H, —CH₃, cyclopropyl,or 4-fluorophenyl; provided that zero or one of R₁ and R₂ is4-fluorophenyl and further provided that at least one of R₁ and R₂ is—CH₃; R₃ is H or F; R₄ is H or F; R₇ is H, —CH₃, or —CH₂CH₃; and Q₂ is—CN, —C(O)CH═CH₂, —C(O)C≡CH, —C(O)C≡CCH₃, —C(O)C≡CCH₂CH₃,—C(O)C≡CCH₂CH₂CH₃, —C(O)C≡C(CH₃)₂(OH), —C(O)C≡CSi(CH₃)₃,—C(O)C≡C(cyclopropyl), —C(O)C≡C(phenyl), or —S(O)₂CH═CH₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

R₁ is H, —CH₃, —CF₃, or 4-fluorophenyl; and R₂ is H, —CH₃, cyclopropyl,or 4-fluorophenyl; provided that zero or one of R₁ and R₂ is4-fluorophenyl and further provided that at least one of R₁ and R₂ is—CH₃; R₃ is H or F; R₄ is H or F; and Q₂ is —CN, —C(O)CH═CH₂,—C(O)C≡CCH₃, or —S(O)₂CH═CH₂. Included in this embodiment are compoundsin which A is:

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is:

R₁ is H, —CH₃, —CF₃, or 4-fluorophenyl; and R₂ is H, —CH₃, cyclopropyl,or 4-fluorophenyl; provided that zero or one of R₁ and R₂ is4-fluorophenyl and further provided that at least one of R₁ and R₂ is—CH₃; R₃ is H or F; R₄ is H or F; R₇ is H; and Q₂ is —CN, —C(O)CH═CH₂,—C(O)≡CH, —C(O)C≡CCH₃, —C(O)CH═CHCH₂N(CH₃)₂, or —S(O)₂CH═CH₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein A is —CHR₈(pyridinyl) wherein each pyridinyl is substituted withR₆ and R₉; R₁ is H, —CH₃, —CF₃, or 4-fluorophenyl; and R₂ is H, —CH₃,cyclopropyl, or 4-fluorophenyl; provided that zero or one of R₁ and R₂is 4-fluorophenyl and further provided that at least one of R₁ and R₂ is—CH₃; R₃ is F; R₄ is H or F; R₆ is H; R₈ is H or —CH₃; and R₉ is —CH═CH₂or —C≡CCH₃.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein: X is N; R₁ is —CH₃; R₂ is —CH₃; R₃ is H, —CN, or —CH₃; A is

Q₂ is —C(O)C═CH₂.

A compound that inhibits an enzyme by reacting with the enzyme to form acovalent bond can offer advantages over a compound that does not formsuch a covalent bond. (See, for example, Liu, Q. et al., Chem. Biol.,20:146 (2013); Barf, T. et al., J Med. Chem., 55:6243 (2012); Kalgutkar,A. et al., Expert Opin. Drug Discov., 7:561 (2012); and Garuti, L. etal., Curr. Med. Chem., 18:2981 (2011); and references cited therein). Acompound that does not form a covalent bond can dissociate from theenzyme, releasing the enzyme from the inhibition resulting from itsbinding. Such reversible inhibition may require a relatively high andcontinuous concentration of the inhibitory compound to drive the bindingequilibrium toward sufficient enzyme occupancy by the inhibitor toachieve useful enzyme inhibition. A higher concentration of the compoundcould require administration of a higher dose of the compound to amammal in need of such inhibition, and at a higher concentration theinhibitor could have undesired effects due to inhibition of other,non-targeted enzymes. Such off-target inhibition could include toxicity.Additionally, more frequent dosing may be required since the inhibitorycompound, after dissociation from the target enzyme, can be removed fromthe body by metabolism and/or elimination, lowering the concentrationavailable to achieve inhibition of the target enzyme.

In contrast, an inhibitor that forms a covalent bond with its targetenzyme irreversibly inhibits the enzyme. The irreversible inhibitionwould result from either slow or negligible dissociation of theinhibitor, since such dissociation would require breaking a covalentbond. If the affinity of such a covalent inhibitor for its target enzymeis sufficiently great relative to affinities for other, off-targetenzymes, a significantly lower concentration of the inhibitor can resultin useful inhibition relative to a concentration required for reversibleinhibition. The lower concentration could reduce the likelihood ofundesired off-target inhibition and potential toxicity. Also, since thecovalent inhibitor can bind essentially irreversibly to the targetenzyme, the free (non-bound) concentration of the inhibitor can becomeextremely low as non-bound inhibitor is removed from the body bymetabolism and/or elimination, even while useful enzyme inhibition ismaintained. This can reduce the likelihood of undesired effects.Additionally, since the enzyme can be irreversibly inhibited, lessfrequent dosing may be required to achieve useful inhibition.

Certain reactive functional groups can be attached to a compound withgood affinity for the target enzyme, which will allow formation ofcovalent bond with a functional group in the target enzyme. For example,an electrophilic group such as a vinylic or acetylenic group attached toan electron-withdrawing group such as a ketone, amide, sulfone,sulfonamide, or an electron-withdrawing heterocyclic ring such as apyridyl ring can react with a nucleophilic group present in the targetenzyme, such as the thiol or thiolate group of a cysteine residue, toform a covalent bond. Such a reaction can be essentially irreversibleunder normal physiological conditions. In order for such a reaction tobe achieved, the inhibitor compound must bind to the target enzyme andpresent the attached electrophilic group in a correct spatialorientation to allow favorable interaction with the attackingnucleophile. If the orientation is not correct, the covalent bond maynot easily form, and the desired irreversible inhibition may not beachieved. In this case, the compound would behave like a reversibleinhibitor and the benefits of irreversible inhibition may not berealized. Also, if the orientation of the electrophile on the boundinhibitor is not suitable for reaction with the nucleophilic group ofthe target enzyme, the inhibitor will be capable of dissociation fromthe target enzyme, resulting in a higher concentration of the inhibitorand a greater likelihood that the reactive electrophilic group can reactwith other, non-target nucleophiles and cause undesired effects such astoxicity.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein said compound covalently bonds to the Btk enzyme.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein Q₁ is —NR₇Q₂, —CR₁₀R₁₀NR₇Q₂, —CH═C(CN)S(O)₂CH₃, or—S(O)₂CH═CR₁₀R₁₀; Q₂ is —C(O)CR₁₀═CR₁₀R₁₀, —C(O)C(R₁₀)═CHCH₂N(CH₃)₂,—C(O)C≡CR₇, —C(O)C≡C(C₁₋₃ hydroxyalkyl), —C(O)C≡C(phenyl),—C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CHR₁₀; and R₁, R₂, R₃, R₄, A, R₇, R₉, andR₁₀ are defined in the first embodiment. Included in this embodiment arecompounds in which R₃ is H, F, or Cl; R₄ is H, F, —OH, —O(C₁₋₂ alkyl),—OCH₂CH₂OCH₃, —OCH₂(phenyl), —OCH₂(methoxyphenyl), or—OCH₂CH₂(morpholinyl); R₅ is H, F, or —CH₃; R₆ is H or F; R₇ is H orC₁₋₃ alkyl; R₈ is H or —CH₃; and R₉ is —CH═CH₂ or —C≡CCH₃.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein Q₁ is —N(CH₃)C(O)CH═CH₂, —N(CH₃)S(O)₂CH═CH₂,—C(CH₃)₂NHS(O)₂CH═CH₂, —CH₂NHC(O)CH═CH₂, —CH₂NHS(O)₂CH═CH₂,—NHC(O)CH═CH₂, —NHC(O)C(CH₃)═CH₂, —NHC(O)CH═C(CH₃)₂, —NHC(O)CH═CHCH₃,—NHC(O)CH═CHCH₂N(CH₃)₂, —NHC(O)(cyclohexenyl), —NHS(O)₂CH═CH₂,—S(O)₂CH═CH₂, or —CH═C(CN)S(O)₂CH₃; and Q₂ is —C(O)CH═CH₂, —S(O)₂CH═CH₂,—C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CH, —C(O)C≡CCH₃, —C(O)C≡CCH₂CH₃,—C(O)C≡CCH₂CH₂CH₃, —C(O)C≡C(CH₃)₂OH, —C(O)C≡CSi(CH₃)₃,—C(O)C≡C(cyclopropyl), or —C(O)C≡C(phenyl); and R₁, R₂, R₃, R₄, and Aare defined in the first embodiment. Included in this embodiment arecompounds in which R₃ is H, F, or Cl; R₄ is H, F, —OH, —O(C₁₋₂ alkyl),—OCH₂CH₂OCH₃, —OCH₂(phenyl), —OCH₂(methoxyphenyl), or—OCH₂CH₂(morpholinyl); R₅ is H, F, or —CH₃; R₆ is H or F; R₇ is H orC₁₋₃ alkyl; R₈ is H or —CH₃; and R₉ is —CH═CH₂ or —C≡CCH₃.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein said compound is4-(3-acrylamido-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide (1);2,3-dimethyl-4-(3-(vinylsulfonyl)phenyl)-1H-indole-7-carboxamide (2);5-fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide(3); 2,3-dimethyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide(4);4-(3-acrylamido-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(5);(E)-4-(3-(but-2-enamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(6); 4-(3-acrylamido-2-methylphenyl)-2-methyl-1H-indole-7-carboxamide(7);(E)-4-(3-(but-2-enamido)-2-methylphenyl)-2-methyl-1H-indole-7-carboxamide(8);(E)-4-(3-(but-2-enamido)-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide(9);2,3-dimethyl-4-(2-methyl-3-(3-methylbut-2-enamido)phenyl)-1H-indole-7-carboxamide(10);2-methyl-4-(2-methyl-3-(3-methylbut-2-enamido)phenyl)-1H-indole-7-carboxamide(11);3-methyl-4-(2-methyl-3-(3-methylbut-2-enamido)phenyl)-1H-indole-7-carboxamide(12);2,3-dimethyl-4-(2-methyl-3-propionamidophenyl)-1H-indole-7-carboxamide(13);4-(3-(cyclopropanecarboxamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(14);4-(3-(1-cyanocyclopropanecarboxamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(15);(E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(16);4-(3-methacrylamido-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(17);4-(3-(cyclohex-1-enecarboxamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(18);4-(3-(2-cyanoacetamido)-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide(19);2,3-dimethyl-4-(2-methyl-3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide(20); 4-(3-((cyanomethyl)carbamoyl)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (21);4-(3-acrylamidophenyl)-2,3-dimethyl-1H-indole-7-carboxamide (22);2,3-dimethyl-4-(2-methyl-3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(23);3-methyl-4-(2-methyl-3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(24);2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(25);5-fluoro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(26);5-chloro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(27);3-methyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(28);2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide(29); 3-methyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide(30);3-methyl-4-(2-methyl-3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide(31);4-(2-fluoro-3-(N-methylacrylamido)phenyl)-2,3-dimethyl-1H-indole-7-carboxamide(32); 3-methyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide(33);2,3-dimethyl-4-(2-methyl-3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide(34);2,3-dimethyl-4-(2-methyl-3-(3-methylene-2-oxopyrrolidin-1-yl)phenyl)-1H-indole-7-carboxamide(35);2,3-dimethyl-4-(3-(3-methylene-2-oxopyrrolidin-1-yl)phenyl)-1H-indole-7-carboxamide(36);5-fluoro-2,3-dimethyl-4-(3-(3-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-1H-indole-7-carboxamide(37); 4-(1-acryloylindolin-6-yl)-2,3-dimethyl-1H-indole-7-carboxamide(38);2,3-dimethyl-4-(1-(vinylsulfonyl)indolin-6-yl)-1H-indole-7-carboxamide(39);2,3-dimethyl-4-(3-(vinylsulfonamidomethyl)phenyl)-1H-indole-7-carboxamide(40);4-(3-(acrylamidomethyl)phenyl)-2,3-dimethyl-1H-indole-7-carboxamide(41);2,3-dimethyl-4-(3-(2-(vinylsulfonamido)propan-2-yl)phenyl)-1H-indole-7-carboxamide(42); 4-(2-acrylamidopyridin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide(43); 4-(2-acrylamidopyridin-4-yl)-2-methyl-1H-indole-7-carboxamide(44); 4-(3-acrylamido-2-methylphenyl)-1H-indole-7-carboxamide (45);4-(2-methyl-3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (46);2,3-dimethyl-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-1H-indole-7-carboxamide(47);4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(48);2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(49);4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(50);4-(3-((5-fluoroquinazolin-4-yl)amino)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(51);4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide(52);4-(3-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide(53);4-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide(54);4-(3-(6-chloro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide(55);4-(3-(8-methoxy-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide(56);4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-1H-indole-7-carboxamide(57);4-(3-(6-cyano-1-oxoisoindolin-2-yl)-2-methylphenyl)-1H-indole-7-carboxamide(58);3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(59);2-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(60);6-((4-methoxybenzyl)oxy)-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(61);4-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole-7-carboxamide(62);4-(3-(6-cyano-1-oxoisoindolin-2-yl)-2-methylphenyl)-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole-7-carboxamide(63);4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole-7-carboxamide(64);4-(3-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole-7-carboxamide(65);4-(3-(8-methoxy-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole-7-carboxamide(66);4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(67);2,3-dimethyl-4-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(68);4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(69);4-(3-(2-cyano-2-(methylsulfonyl)vinyl)phenyl)-2,3-dimethyl-1H-indole-7-carboxamide(70);6-hydroxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(71);6-ethoxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(72);6-methoxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(73);6-(benzyloxy)-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(74);2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-6-(2-morpholinoethoxy)-1H-indole-7-carboxamide(75);6-(2-methoxyethoxy)-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(76);4-(3-((4,6-dichloro-1,3,5-triazin-2-yl)amino)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(77);(RS)-2,3-dimethyl-4-(3-(N-methylacrylamido)piperidin-1-yl)-1H-indole-7-carboxamide(78);4-((1-acryloylpiperidin-4-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(79); 4-(1-acryloylpiperidin-3-yl)-2,3-dimethyl-1H-indole-7-carboxamide(80);(R)-4-(3-acrylamidopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(81);4-(3-acrylamidopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(82);4-(3-acrylamidopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(83);(S)-4-(3-acrylamidopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(84);(R)-4-(3-acrylamidopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(85);4-((1-acryloylpyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(86);(R)-4-((1-acryloylpyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(87);(S)-4-((1-acryloylpyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(88);(S)-4-(3-acrylamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(89); 4-(1-acryloylpyrrolidin-3-yl)-2,3-dimethyl-1H-indole-7-carboxamide(90);4-((1-acryloylpiperidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(91);4-((1-acryloylpiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(92); 4-(1-acryloylpiperidin-3-yl)-3-methyl-1H-indole-7-carboxamide(93);(S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(94);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(95);(S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(96);4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(97); cis-4-(5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(98);4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(99);(S)-4-(3-acrylamidopyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(100);4-(2-acryloylisoindolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(101);(RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(102);(RS)-2,3-dimethyl-4-((1-propioloylpyrrolidin-3-yl)amino)-1H-indole-7-carboxamide(103);(RS)-4-(1-(but-2-ynoyl)piperidin-3-yl)-3-methyl-1H-indole-7-carboxamide(104);2,3-dimethyl-4-(3-(N-methylpropiolamido)piperidin-1-yl)-1H-indole-7-carboxamide(105);2,3-dimethyl-4-((1-propioloylpiperidin-3-yl)amino)-1H-indole-7-carboxamide(106);4-((1-(but-2-ynoyl)piperidin-4-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(107);2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide(108);(S)-2,3-dimethyl-4-(3-(3-phenylpropiolamido)piperidin-1-yl)-1H-indole-7-carboxamide(109);(S)-2,3-dimethyl-4-(3-(3-(trimethylsilyl)propiolamido)piperidin-1-yl)-1H-indole-7-carboxamide(110);(S)-4-(3-(4-hydroxy-4-methylpent-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(111); (S)-2,3-dimethyl-4-(3-(pent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (112);(S)-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(113);2,3-dimethyl-4-((1-propioloylpiperidin-4-yl)amino)-1H-indole-7-carboxamide(114);(S)-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide(115);(S)-4-(3-(but-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(116);(R)-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide(117);(R)-4-(3-(but-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(118);(R)-2,3-dimethyl-4-(3-propiolamidopyrrolidin-1-yl)-1H-indole-7-carboxamide(119);(R)-4-(3-(but-2-ynamido)pyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(120);4-((1-(but-2-ynoyl)pyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(121);4-((1-(but-2-ynoyl)piperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(122);(S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(123);(S,E)-4-((1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(124);(S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide(125); (S)-5-fluoro-2,3-dimethyl-4-(3-(pent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (126);(S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylpent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide(127);(S)-5-fluoro-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(128);4-(2-(but-2-ynoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(129);(S)-4-(3-(N-ethylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(130);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(131);(RS)-4-(2-acryloylisoindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(132);(RS)-4-(2-(but-2-ynoyl)isoindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(133);4-(2-(but-2-ynoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(134);(S)-4-(3-(but-2-ynamido)pyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(135);(S)-4-(3-(3-cyclopropylpropiolamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(136);4-(2-(but-2-ynoyl)isoindolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(137);(RS)-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide(138);2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide(139);2,3-dimethyl-4-(3-(vinylsulfonamido)pyrrolidin-1-yl)-1H-indole-7-carboxamide(140);(S)-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide(141);(R)-2,3-dimethyl-4-(3-(vinylsulfonamido)pyrrolidin-1-yl)-1H-indole-7-carboxamide(142);(R)-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide(143);2,3-dimethyl-4-((1-(vinylsulfonyl)pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide(144);2,3-dimethyl-4-(4-(vinylsulfonyl)piperazin-1-yl)-1H-indole-7-carboxamide(145);(S)-5-fluoro-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide(146);(S)-4-((1-cyanopyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(147); 4-(1-cyanopiperidin-3-yl)-2,3-dimethyl-1H-indole-7-carboxamide(148); 4-(1-cyanopyrrolidin-3-yl)-2,3-dimethyl-1H-indole-7-carboxamide(149);(S)-4-(3-cyanamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(150);4-((1-cyanopiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(151);4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(152);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (153 and 154);4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (155 and 156);4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (157 and 158);cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (159 and 160);cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single diastereomers (161 through 164); 4-(5-acryloylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (165 and 166);4-(1-acryloylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (167 and 168);4-(2-acryloyl-4-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single diastereomers (169 through 172);cis-4-(1-(but-2-ynoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (173 and 174);4-(5-(but-2-ynoyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (175 and 176);4-(1-(but-2-ynoyl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (177 and 178);cis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (179 and 180);5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide(181);5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carboxamide(182);5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carboxamide,single enantiomers (183 and 184);5-fluoro-2,3-dimethyl-4-((2-vinylpyridin-4-yl)methyl)-1H-indole-7-carboxamide(185);(RS)-4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(186);4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (187 and 188);(RS)-4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(189);4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (190 and 191);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(192);(RS)-4-(1-acryloylindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(193);(RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(194);4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (195 and 196);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(197);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide,single enantiomers (198 and 199);(S)-4-(3-(N-cyclopropylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(200);4-(4-(but-2-ynoyl)piperazin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(201);4-(4-acryloylpiperazin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(202);4-(2-(but-2-ynoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(203);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(204);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (205 and 206);4-(1-acryloylindolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(207);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-6-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(208);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide(209);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide,single enantiomers (210 and 211);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide(212);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide,single enantiomers (213 and 214);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indole-7-carboxamide(215);4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(216);(RS)-4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(217);4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (218 and 219); (RS)-4-(1-(but-2-ynoyl)piperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (220);5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carboxamide(221);5-fluoro-4-((5-fluoro-6-vinylpyridin-3-yl)methyl)-2,3-dimethyl-1H-indole-7-carboxamide(222);(S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(223);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iodo-2,3-dimethyl-1H-indole-7-carboxamide(224);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(225);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(226);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(227 and 228);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-cyano-2,3-dimethyl-1H-indole-7-carboxamide(229);4-((1-acryloylpiperidin-4-yl)methyl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(230);4-(2-acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(231 and 232);4-(1-acryloyl-1,4,5,6-tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(233);4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(234);4-(1-acryloyl-2,5-dihydro-1H-pyrrol-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(235);4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(236);4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(237);4-(1-(but-2-ynoyl)-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(238);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide,racemate (239);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide,atropisomer A (240);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide(241);(S)-5-fluoro-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide(242);(R)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(243);4-(6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(244);4-(6-(but-2-ynoyl)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(245);4-(7-acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(246);4-(7-(but-2-ynoyl)-2,7-diazaspiro[4.4]nonan-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(247);5-fluoro-2,3-dimethyl-4-(2-vinylpyridin-3-yl)-1H-indole-7-carboxamide(248);5-fluoro-3-methyl-2-(trifluoromethyl)-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide(249);4-(1-acryloylpyrrolidin-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(250);4-(1-acryloylpyrrolidin-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(251);4-(1-acryloylpyrrolidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(252);5-fluoro-2,3-dimethyl-4-(3-vinyl-5,6-dihydroisoquinolin-8-yl)-1H-indole-7-carboxamide(253);4-(1-(but-2-ynoyl)-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(254);4-(1-acryloyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(255);4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(256);4-((1-acryloylpiperidin-4-ylidene)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(257);4-((1-acryloylpiperidin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(258);4-((1-acryloylpyrrolidin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(259);4-((1-(but-2-ynoyl)piperidin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(260); 4-((1-(but-2-ynoyl)piperidin-4-ylidene)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (261);4-((1-(but-2-ynoyl)pyrrolidin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(262);5-fluoro-4-(3-fluoro-2-vinylpyridin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide(263);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide,atropisomer B (264); or4-(2-(but-2-ynoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide(265).

One embodiment provides a compound of Formula (I) or a salt thereof,wherein said compound is4-(3-acrylamido-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide (1);2,3-dimethyl-4-(3-(vinylsulfonyl)phenyl)-1H-indole-7-carboxamide (2);5-fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide(3); 2,3-dimethyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide(4);4-(3-acrylamido-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(5); 4-(3-acrylamido-2-methylphenyl)-2-methyl-1H-indole-7-carboxamide(7);(E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(16);2,3-dimethyl-4-(2-methyl-3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide(20); 4-(3-acrylamidophenyl)-2,3-dimethyl-1H-indole-7-carboxamide (22);2,3-dimethyl-4-(2-methyl-3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(23);3-methyl-4-(2-methyl-3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(24);2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(25); 5-fluoro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (26);5-chloro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(27);3-methyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide(28);2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide(29); 3-methyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide(30);3-methyl-4-(2-methyl-3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide(31);4-(2-fluoro-3-(N-methylacrylamido)phenyl)-2,3-dimethyl-1H-indole-7-carboxamide(32); 3-methyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide(33);2,3-dimethyl-4-(2-methyl-3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide(34); 4-(1-acryloylindolin-6-yl)-2,3-dimethyl-1H-indole-7-carboxamide(38);2,3-dimethyl-4-(1-(vinylsulfonyl)indolin-6-yl)-1H-indole-7-carboxamide(39); (RS)-2,3-dimethyl-4-(3-(N-methylacrylamido)piperidin-1-yl)-1H-indole-7-carboxamide (78);4-((1-acryloylpiperidin-4-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(79); 4-(1-acryloylpiperidin-3-yl)-2,3-dimethyl-1H-indole-7-carboxamide(80);4-(3-acrylamidopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(82);4-(3-acrylamidopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(83);4-((1-acryloylpyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(86);(S)-4-((1-acryloylpyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(88);(S)-4-(3-acrylamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(89);4-((1-acryloylpiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(92); 4-(1-acryloylpiperidin-3-yl)-3-methyl-1H-indole-7-carboxamide(93);(S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-2,3-dimethyl-1H-indole-7-carboxamide(94);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(95);(S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(96);4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(97);cis-4-(5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(98);4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(99);(S)-4-(3-acrylamidopyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(100);(RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(102);(RS)-2,3-dimethyl-4-((1-propioloylpyrrolidin-3-yl)amino)-1H-indole-7-carboxamide(103);2,3-dimethyl-4-(3-(N-methylpropiolamido)piperidin-1-yl)-1H-indole-7-carboxamide(105); 2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (108);(S)-2,3-dimethyl-4-(3-(3-phenylpropiolamido)piperidin-1-yl)-1H-indole-7-carboxamide(109);(S)-2,3-dimethyl-4-(3-(3-(trimethylsilyl)propiolamido)piperidin-1-yl)-1H-indole-7-carboxamide(110);(S)-4-(3-(4-hydroxy-4-methylpent-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(111);(S)-2,3-dimethyl-4-(3-(pent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide(112);(S)-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(113);2,3-dimethyl-4-((1-propioloylpiperidin-4-yl)amino)-1H-indole-7-carboxamide(114);(S)-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide(115);(S)-4-(3-(but-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(116);(R)-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide(117);(R)-4-(3-(but-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(118);(R)-2,3-dimethyl-4-(3-propiolamidopyrrolidin-1-yl)-1H-indole-7-carboxamide(119);(R)-4-(3-(but-2-ynamido)pyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(120);(S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(123); (S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (125);(S)-5-fluoro-2,3-dimethyl-4-(3-(pent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide(126);(S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylpent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide(127);(S)-5-fluoro-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(128);(S)-4-(3-(N-ethylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(130);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(131);(RS)-4-(2-acryloylisoindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(132);(S)-4-(3-(but-2-ynamido)pyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(135);(S)-4-(3-(3-cyclopropylpropiolamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(136);(RS)-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide(138);2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide(139);2,3-dimethyl-4-(3-(vinylsulfonamido)pyrrolidin-1-yl)-1H-indole-7-carboxamide(140);(S)-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide(141);(R)-2,3-dimethyl-4-(3-(vinylsulfonamido)pyrrolidin-1-yl)-1H-indole-7-carboxamide(142); (R)-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (143);2,3-dimethyl-4-((1-(vinylsulfonyl)pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide (144);2,3-dimethyl-4-(4-(vinylsulfonyl)piperazin-1-yl)-1H-indole-7-carboxamide(145);(S)-5-fluoro-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide(146);(S)-4-((1-cyanopyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(147);(S)-4-(3-cyanamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(150);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (153 and 154);4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (155 and 156);cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (159 and 160);cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single diastereomers (161 and 164);4-(5-acryloylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (165 and 166);4-(1-acryloylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (167 and 168);4-(2-acryloyl-4-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single diastereomers (170 through 172);cis-4-(1-(but-2-ynoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (173 and 174); 4-(1-(but-2-ynoyl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (177 and 178);5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide(181);5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carboxamide(182);5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carboxamide,single enantiomers (183 and 184);5-fluoro-2,3-dimethyl-4-((2-vinylpyridin-4-yl)methyl)-1H-indole-7-carboxamide(185);(RS)-4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(186);4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomer (188);(RS)-4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(189);4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomer (191);(RS)-4-(1-acryloylindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(193);(RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(194);4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (195 and 196);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(197);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide,single enantiomer (199);(S)-4-(3-(N-cyclopropylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(200);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(204);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomer (206);4-(1-acryloylindolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(207);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-6-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(208);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide(209);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide,single enantiomer (211);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide(212);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide,single enantiomer (213);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indole-7-carboxamide(215);4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(216);(RS)-4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(217); or4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomer (219).

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₃ is F and said compound is5-fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide(3); 5-fluoro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (26);5-fluoro-2,3-dimethyl-4-(3-(3-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-1H-indole-7-carboxamide(37);(S)-4-((1-acryloylpyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(88);(S)-4-(3-acrylamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(89);4-((1-acryloylpiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(92);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(95);(S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(96);4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(97);cis-4-(5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(98);4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(99);(S)-4-(3-acrylamidopyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(100);4-(2-acryloylisoindolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(101);(RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(102);4-((1-(but-2-ynoyl)piperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(122);(S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(123);(S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide(125); (S)-5-fluoro-2,3-dimethyl-4-(3-(pent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (126);(S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylpent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide(127);(S)-5-fluoro-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide(128);4-(2-(but-2-ynoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(129);(S)-4-(3-(N-ethylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(130);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(131);(RS)-4-(2-acryloylisoindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(132);(RS)-4-(2-(but-2-ynoyl)isoindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(133);4-(2-(but-2-ynoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(134);(S)-4-(3-(but-2-ynamido)pyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(135);(S)-4-(3-(3-cyclopropylpropiolamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(136);4-(2-(but-2-ynoyl)isoindolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(137);(S)-5-fluoro-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide(146);(S)-4-((1-cyanopyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(147);(S)-4-(3-cyanamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(150);4-((1-cyanopiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(151);4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(152);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (153 and 154);4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (155 and 156);4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (157 and 158);cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (159 and 160);cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single diastereomers (161 through 164); 4-(5-acryloylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (165 and 166);4-(1-acryloylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (167 and 168);4-(2-acryloyl-4-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single diastereomers (169 through 172);cis-4-(1-(but-2-ynoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (173 and 174);4-(5-(but-2-ynoyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (175 and 176);4-(1-(but-2-ynoyl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (177 and 178);cis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (179 and 180);5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide(181);5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carboxamide(182);5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carboxamide,single enantiomers (183 and 184);5-fluoro-2,3-dimethyl-4-((2-vinylpyridin-4-yl)methyl)-1H-indole-7-carboxamide(185);(RS)-4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(186);4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (187 and 188);(RS)-4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(189);4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (190 and 191);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(192);(RS)-4-(1-acryloylindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(193);(RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(194);4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (195 and 196);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(197);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide,single enantiomers (198 and 199);(S)-4-(3-(N-cyclopropylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(200);4-(4-(but-2-ynoyl)piperazin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(201);4-(4-acryloylpiperazin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(202);4-(2-(but-2-ynoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(203);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(204);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (205 and 206); or4-(1-acryloylindolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(207); One embodiment provides a compound of Formula (I) or a saltthereof, wherein R₃ is F and said compound is(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide(212);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide,single enantiomers (213 and 214);(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indole-7-carboxamide(215);4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(216);(RS)-4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(217);4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,single enantiomers (218 and 219); (RS)-4-(1-(but-2-ynoyl)piperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (220);5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carboxamide(221); or5-fluoro-4-((5-fluoro-6-vinylpyridin-3-yl)methyl)-2,3-dimethyl-1H-indole-7-carboxamide(222).

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₃ is F and said compound is(S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(223);4-((1-acryloylpiperidin-4-yl)methyl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(230);4-(2-acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(231 and 232);4-(1-acryloyl-1,4,5,6-tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(233);4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(234);4-(1-acryloyl-2,5-dihydro-1H-pyrrol-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(235);4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(236);4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(237);4-(1-(but-2-ynoyl)-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(238);(S)-5-fluoro-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide(242);(R)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(243);4-(6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(244);4-(6-(but-2-ynoyl)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(245);4-(7-acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(246);4-(7-(but-2-ynoyl)-2,7-diazaspiro[4.4]nonan-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(247);5-fluoro-2,3-dimethyl-4-(2-vinylpyridin-3-yl)-1H-indole-7-carboxamide(248);5-fluoro-3-methyl-2-(trifluoromethyl)-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide(249);4-(1-acryloylpyrrolidin-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(250);4-(1-acryloylpyrrolidin-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(251);4-(1-acryloylpyrrolidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(252);5-fluoro-2,3-dimethyl-4-(3-vinyl-5,6-dihydroisoquinolin-8-yl)-1H-indole-7-carboxamide(253);4-(1-(but-2-ynoyl)-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(254);4-(1-acryloyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(255);4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(256);4-((1-acryloylpiperidin-4-ylidene)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(257);4-((1-acryloylpiperidin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(258);4-((1-acryloylpyrrolidin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(259);4-((1-(but-2-ynoyl)piperidin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(260);4-((1-(but-2-ynoyl)piperidin-4-ylidene)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(261);4-((1-(but-2-ynoyl)pyrrolidin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(262); or5-fluoro-4-(3-fluoro-2-vinylpyridin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide(263).

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₃ is Cl and said compound is5-chloro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (27);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide,racemate (239);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide,atropisomer A (240);4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide,atropisomer B (264); or4-(2-(but-2-ynoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide(265).

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of the aspects and/or embodimentsof the invention noted herein. It is understood that any and allembodiments of the present invention may be taken in conjunction withany other embodiment or embodiments to describe additional embodiments.It is also to be understood that each individual element of theembodiments is meant to be combined with any and all other elements fromany embodiment to describe an additional embodiment.

Definitions

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. Embodiments identified herein as exemplary or preferred areintended to be illustrative and not limiting.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

As used herein, the phase “compounds” refers to at least one compound.For example, a compound of Formula (I) includes a compound of Formula(I) and two or more compounds of Formula (I).

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Listed below are definitions of various terms used to describe thepresent invention. These definitions apply to the terms as they are usedthroughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

The term “alkyl” as used herein, refers to both branched andstraight-chain saturated aliphatic hydrocarbon groups containing, forexample, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1to 4 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl(e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscriptafter the symbol “C”, the subscript defines with more specificity thenumber of carbon atoms that a particular group may contain. For example,“C₁₋₄alkyl” denotes straight and branched chain alkyl groups with one tofour carbon atoms.

The term “hydroxyalkyl” refers to both branched and straight-chainsaturated alkyl groups substituted with one or more hydroxyl groups. Forexample, “hydroxyalkyl” includes —CH₂OH, —CH₂CH₂OH, and C₁₋₄hydroxyalkyl. “C₁₋₄ hydroxyalkyl” is intended to include C₁, C₂, C₃, andC₄ alkyl groups substituted with one or more hydroxyl groups.

As used herein, “alkylene” refers to a bivalent alkyl radical having thegeneral formula —(CH₂)_(n)—, where n is 1 to 10. Non-limiting examplesinclude methylene, dimethylene, trimethylene, tetramethylene,pentamethylene, and hexamethylene. For example, “C₁₋₆ alkylene” denotesstraight and branched chain alkylene groups with one to six carbonatoms. Further, for example, “C₀₋₄ alkylene” denotes a bond and straightand branched chain alkylene groups with one to four carbon atoms.

The term “cyano” refers to the group —CN.

The term “cycloalkyl”, as used herein, refers to a group derived from anon-aromatic monocyclic or polycyclic hydrocarbon molecule by removal ofone hydrogen atom from a saturated ring carbon atom. Representativeexamples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in asubscript after the symbol “C”, the subscript defines with morespecificity the number of carbon atoms that a particular cycloalkylgroup may contain. For example, “C₃₋₆ cycloalkyl” denotes cycloalkylgroups with three to six carbon atoms.

The term “cycloalkenyl”, as used herein, refers to a cyclic hydrocarbonsring having 1 double bond. For example, “C₅₋₆ cycloalkenyl” denotescyclopentenyl and cyclohexenyl.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of Formula (I) can be provided as amorphous solids orcrystalline solids. Lyophilization can be employed to provide thecompounds of Formula (I) as amorphous solids.

Certain compounds of Formula (I) may exist in a free form (with noionization) or can form salts which are also within the scope of thisinvention. Unless otherwise indicated, reference to an inventivecompound is understood to include reference to the free form and tosalts thereof. The term “salt(s)” denotes acidic salts formed withinorganic and/or organic acids. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred, such as, forexample, salts in which the anion does not contribute significantly tothe toxicity or biological activity of the salt. However, other saltsmay be useful, e.g., in isolation or purification steps which may beemployed during preparation, and thus, are contemplated within the scopeof the invention. Salts of the compounds of the Formula (I) may beformed, for example, by reacting a compound of the Formula (I) with anamount of acid such as an equivalent amount, in a medium such as one inwhich the salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

It should further be understood that solvates (e.g., hydrates) of thecompounds of Formula (I) are also within the scope of the presentinvention. The term “solvate” means a physical association of a compoundof Formula (I) with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for example,when one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, ethanolates, methanolates, isopropanolates, acetonitrilesolvates, and ethyl acetate solvates. Methods of solvation are known inthe art.

Various forms of prodrugs are well known in the art and are describedin:

-   -   a) Wermuth, C. G. et al., The Practice of Medicinal Chemistry,        Chapter 31, Academic Press (1996);    -   b) Bundgaard, H. ed., Design of Prodrugs, Elsevier (1985);    -   c) Bundgaard, H., Chapter 5, “Design and Application of        Prodrugs”, A Textbook of Drug Design and Development, pp.        113-191, Krogsgaard-Larsen, P. et al., eds., Harwood Academic        Publishers (1991); and    -   d) Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism,        Wiley-VCH (2003).

In addition, compounds of Formula (I), subsequent to their preparation,can be isolated and purified to obtain a composition containing anamount by weight equal to or greater than 99% of a compound of Formula(I) (“substantially pure”), which is then used or formulated asdescribed herein. Such “substantially pure” compounds of Formula (I) arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to act as aninhibitor to Btk, or effective to treat or prevent autoimmune and/orinflammatory and/or proliferative disease states, such as multiplesclerosis and rheumatoid arthritis.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

The compounds of the present invention are intended to include allisotopes of atoms occurring in the present compounds. Isotopes includethose atoms having the same atomic number but different mass numbers. Byway of general example and without limitation, isotopes of hydrogeninclude deuterium (D) and tritium (T). Isotopes of carbon include ¹³Cand ¹⁴C. Isotopically-labeled compounds of the invention can generallybe prepared by conventional techniques known to those skilled in the artor by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed. For example, methyl (—CH₃) also includesdeuterated methyl groups such as —CD₃.

Compounds in accordance with Formula (I) can be administered by anymeans suitable for the condition to be treated, which can depend on theneed for site-specific treatment or quantity of Formula (I) compound tobe delivered.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising a compound of Formula (I) and one or morenon-toxic, pharmaceutically-acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) and,if desired, other active ingredients. The compounds of Formula (I) maybe administered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, or parentally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly, and intrastemally indosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. For example, thepharmaceutical carrier may contain a mixture of mannitol or lactose andmicrocrystalline cellulose. The mixture may contain additionalcomponents such as a lubricating agent, e.g., magnesium stearate and adisintegrating agent such as crospovidone. The carrier mixture may befilled into a gelatin capsule or compressed as a tablet. Thepharmaceutical composition may be administered as an oral dosage form oran infusion, for example.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, liquid capsule, suspension, orliquid. The pharmaceutical composition is preferably made in the form ofa dosage unit containing a particular amount of the active ingredient.For example, the pharmaceutical composition may be provided as a tabletor capsule comprising an amount of active ingredient in the range offrom about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, andmore preferably from about 0.5 to 100 mg. A suitable daily dose for ahuman or other mammal may vary widely depending on the condition of thepatient and other factors, but, can be determined using routine methods.

Any pharmaceutical composition contemplated herein can, for example, bedelivered orally via any acceptable and suitable oral preparations.Exemplary oral preparations, include, but are not limited to, forexample, tablets, troches, lozenges, aqueous and oily suspensions,dispersible powders or granules, emulsions, hard and soft capsules,liquid capsules, syrups, and elixirs. Pharmaceutical compositionsintended for oral administration can be prepared according to anymethods known in the art for manufacturing pharmaceutical compositionsintended for oral administration. In order to provide pharmaceuticallypalatable preparations, a pharmaceutical composition in accordance withthe invention can contain at least one agent selected from sweeteningagents, flavoring agents, coloring agents, demulcents, antioxidants, andpreserving agents.

A tablet can, for example, be prepared by admixing at least one compoundof Formula (I) with at least one non-toxic pharmaceutically acceptableexcipient suitable for the manufacture of tablets. Exemplary excipientsinclude, but are not limited to, for example, inert diluents, such as,for example, calcium carbonate, sodium carbonate, lactose, calciumphosphate, and sodium phosphate; granulating and disintegrating agents,such as, for example, microcrystalline cellulose, sodium croscarmellose,corn starch, and alginic acid; binding agents, such as, for example,starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricatingagents, such as, for example, magnesium stearate, stearic acid, andtalc. Additionally, a tablet can either be uncoated, or coated by knowntechniques to either mask the bad taste of an unpleasant tasting drug,or delay disintegration and absorption of the active ingredient in thegastrointestinal tract thereby sustaining the effects of the activeingredient for a longer period. Exemplary water soluble taste maskingmaterials, include, but are not limited to,hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplarytime delay materials, include, but are not limited to, ethyl celluloseand cellulose acetate butyrate.

Hard gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one inert solid diluent, suchas, for example, calcium carbonate; calcium phosphate; and kaolin.

Soft gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one water soluble carrier,such as, for example, polyethylene glycol; and at least one oil medium,such as, for example, peanut oil, liquid paraffin, and olive oil.

An aqueous suspension can be prepared, for example, by admixing at leastone compound of Formula (I) with at least one excipient suitable for themanufacture of an aqueous suspension. Exemplary excipients suitable forthe manufacture of an aqueous suspension, include, but are not limitedto, for example, suspending agents, such as, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth,and gum acacia; dispersing or wetting agents, such as, for example, anaturally-occurring phosphatide, e.g., lecithin; condensation productsof alkylene oxide with fatty acids, such as, for example,polyoxyethylene stearate; condensation products of ethylene oxide withlong chain aliphatic alcohols, such as, for example,heptadecaethylene-oxycetanol; condensation products of ethylene oxidewith partial esters derived from fatty acids and hexitol, such as, forexample, polyoxyethylene sorbitol monooleate; and condensation productsof ethylene oxide with partial esters derived from fatty acids andhexitol anhydrides, such as, for example, polyethylene sorbitanmonooleate. An aqueous suspension can also contain at least onepreservative, such as, for example, ethyl and n-propylp-hydroxybenzoate; at least one coloring agent; at least one flavoringagent; and/or at least one sweetening agent, including but not limitedto, for example, sucrose, saccharin, and aspartame.

Oily suspensions can, for example, be prepared by suspending at leastone compound of Formula (I) in either a vegetable oil such as, forexample, arachis oil, olive oil, sesame oil and coconut oil; or inmineral oil such as, for example, liquid paraffin. An oily suspensioncan also contain at least one thickening agent such as, for example,beeswax, hard paraffin and cetyl alcohol. In order to provide apalatable oily suspension, at least one of the sweetening agents alreadydescribed hereinabove, and/or at least one flavoring agent can be addedto the oily suspension. An oily suspension can further contain at leastone preservative, including, but not limited to, for example, anantioxidant, such as, for example, butylated hydroxyanisol andalpha-tocopherol.

Dispersible powders and granules can, for example, be prepared byadmixing at least one compound of Formula (I) with at least onedispersing and/or wetting agent; at least one suspending agent; and/orat least one preservative. Suitable dispersing agents, wetting agents,and suspending agents are as already described above. Exemplarypreservatives include, but are not limited to, for example,anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders andgranules can also contain at least one excipient, including, but notlimited to, for example, sweetening agents; flavoring agents; andcoloring agents.

An emulsion of at least one compound of Formula (I) can, for example, beprepared as an oil-in-water emulsion. The oily phase of the emulsionscomprising compounds of Formula (I) may be constituted from knowningredients in a known manner. The oil phase can be provided by, but isnot limited to, for example, a vegetable oil, such as, for example,olive oil and arachis oil; a mineral oil, such as, for example, liquidparaffin; and mixtures thereof. While the phase may comprise merely anemulsifier, it may comprise a mixture of at least one emulsifier with afat or an oil or with both a fat and an oil. Suitable emulsifying agentsinclude, but are not limited to, for example, naturally-occurringphosphatides, e.g., soy bean lecithin; esters or partial esters derivedfrom fatty acids and hexitol anhydrides, such as, for example, sorbitanmonooleate; and condensation products of partial esters with ethyleneoxide, such as, for example, polyoxyethylene sorbitan monooleate.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations. Anemulsion can also contain a sweetening agent, a flavoring agent, apreservative, and/or an antioxidant. Emulsifiers and emulsionstabilizers suitable for use in the formulation of the present inventioninclude Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol,glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate aloneor with a wax, or other materials well known in the art.

The compounds of Formula (I) can, for example, also be deliveredintravenously, subcutaneously, and/or intramuscularly via anypharmaceutically acceptable and suitable injectable form. Exemplaryinjectable forms include, but are not limited to, for example, sterileaqueous solutions comprising acceptable vehicles and solvents, such as,for example, water, Ringer's solution, and isotonic sodium chloridesolution; sterile oil-in-water microemulsions; and aqueous or oleaginoussuspensions.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (i.e., CAPTISOL®), co-solvent solubilization (i.e.,propylene glycol) or micellar solubilization (i.e., Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

A sterile injectable oil-in-water microemulsion can, for example, beprepared by 1) dissolving at least one compound of Formula (I) in anoily phase, such as, for example, a mixture of soybean oil and lecithin;2) combining the Formula (I) containing oil phase with a water andglycerol mixture; and 3) processing the combination to form amicroemulsion.

A sterile aqueous or oleaginous suspension can be prepared in accordancewith methods already known in the art. For example, a sterile aqueoussolution or suspension can be prepared with a non-toxicparenterally-acceptable diluent or solvent, such as, for example,1,3-butane diol; and a sterile oleaginous suspension can be preparedwith a sterile non-toxic acceptable solvent or suspending medium, suchas, for example, sterile fixed oils, e.g., synthetic mono- ordiglycerides; and fatty acids, such as, for example, oleic acid.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that maybe used in the pharmaceutical compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants usedin pharmaceutical dosage forms such as Tweens, polyethoxylated castoroil such as CREMOPHOR® surfactant (BASF), or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin,or chemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals. The pharmaceutical compositions may be subjected toconventional pharmaceutical operations such as sterilization and/or maycontain conventional adjuvants, such as preservatives, stabilizers,wetting agents, emulsifiers, buffers etc. Tablets and pills canadditionally be prepared with enteric coatings. Such compositions mayalso comprise adjuvants, such as wetting, sweetening, flavoring, andperfuming agents.

The amounts of compounds that are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex, the medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.001 to 100 mg/kg body weight, preferably between about0.0025 and about 50 mg/kg body weight and most preferably between about0.005 to 10 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day. Other dosing schedulesinclude one dose per week and one dose per two day cycle.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered orally, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

Pharmaceutical compositions of this invention comprise at least onecompound of Formula (I) and optionally an additional agent selected fromany pharmaceutically acceptable carrier, adjuvant, and vehicle.Alternate compositions of this invention comprise a compound of theFormula (I) described herein, or a prodrug thereof, and apharmaceutically acceptable carrier, adjuvant, or vehicle.

Utility

The compounds of the invention modulate kinase activity, including themodulation of Btk. Other types of kinase activity that may be modulatedby the compounds of the instant invention include, but are not limitedto, the Tec family of kinases, such as BMX, Btk, ITK, TXK and Tec, andmutants thereof.

Accordingly, compounds of Formula (I) have utility in treatingconditions associated with the modulation of kinase activity, andparticularly the selective inhibition of Btk activity. Such conditionsinclude B-cell mediated diseases in which cytokine levels are modulatedas a consequence of intracellular signaling.

As used herein, the terms “treating” or “treatment” encompass either orboth responsive and prophylaxis measures, e.g., measures designed toinhibit or delay the onset of the disease or disorder, achieve a full orpartial reduction of the symptoms or disease state, and/or to alleviate,ameliorate, lessen, or cure the disease or disorder and/or its symptoms.

In view of their activity as selective inhibitors of Btk, compounds ofFormula (I) are useful in treating cytokine-associated conditionsincluding, but not limited to, inflammatory diseases such as Crohn's andulcerative colitis, asthma, graft versus host disease and chronicobstructive pulmonary disease; autoimmune diseases such as Graves'disease, rheumatoid arthritis, systemic lupus erythematosis andpsoriasis; destructive bone disorders such as bone resorption disease,osteoarthritis, osteoporosis and multiple myeloma-related bone disorder;proliferative disorders such as acute myelogenous leukemia and chronicmyelogenous leukemia; angiogenic disorders such as solid tumors, ocularneovasculization, and infantile haemangiomas; infectious diseases suchas sepsis, septic shock, and shigellosis; neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, cerebral ischemias orneurodegenerative disease caused by traumatic injury, oncologic andviral diseases such as metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, HIV infection, AIDS and CMV retinitis.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis,scleroderma, Sjögren's syndrome, chronic thyroiditis, Graves' disease,autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmuneneutropenia, thrombocytopenia, atopic dermatitis, chronic activehepatitis, myasthenia gravis, multiple sclerosis, inflammatory boweldisease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. hostdisease, inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, Kawasaki disease, chronic inflammatorydemyelinating polyneuropathy (CIDP), dermatomyositis, uveitis,anti-factor-VIII disease, ankylosing spondylitis, myasthenia gravis,Goodpasture's disease, antiphospholipid syndrome, ANCA-associatedvasculitis, dermatomyositis/polymyositis, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, boneresorption disease, allograft rejections, fever and myalgias due toinfection, cachexia secondary to infection, myeloid formation, scartissue formation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hypoxia, vascular hyperplasia, cardiac and renalreperfusion injury, thrombosis, cardiac hypertrophy, thrombin-inducedplatelet aggregation, endotoxemia and/or toxic shock syndrome,conditions associated with prostaglandin endoperoxidase syndase-2, andpemphigus vulgaris.

Preferred methods of treatment are those wherein the condition isselected from Crohn's and ulcerative colitis, allograft rejection,rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriaticarthritis, pemphigus vulgaris and multiple sclerosis. Alternativelypreferred methods of treatment are those wherein the condition isselected from ischemia reperfusion injury, including cerebral ischemiareperfusions injury arising from stroke and cardiac ischemia reperfusioninjury arising from myocardial infarction. Another preferred method oftreatment is one in which the condition is multiple myeloma.

In addition, the Btk inhibitors of the present invention inhibit theexpression of inducible pro-inflammatory proteins such as prostaglandinendoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2(COX-2). Accordingly, additional Btk-associated conditions includeedema, analgesia, fever and pain, such as neuromuscular pain, headache,pain caused by cancer, dental pain and arthritis pain. The inventivecompounds also may be used to treat veterinary viral infections, such aslentivirus infections, including, but not limited to equine infectiousanemia virus; or retro virus infections, including felineimmunodeficiency virus, bovine immunodeficiency virus, and canineimmunodeficiency virus.

When the terms “Btk-associated condition” or “Btk-associated disease ordisorder” are used herein, each is intended to encompass all of theconditions identified above as if repeated at length, as well as anyother condition that is affected by Btk kinase activity.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit Btk.

One embodiment provides methods for treating such Btk kinase-associatedconditions, comprising administering to a subject in need thereof atleast one compound of Formula (I). A therapeutically-effective amountfor treating such conditions may be administered. The methods of thepresent embodiment may be employed to treat Btk kinase-associatedconditions such as treatment of allergic disorders and/or autoimmuneand/or inflammatory diseases including, but not limited to, SLE,rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenicpurpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis(MS), transplant rejection, Type I diabetes, membranous nephritis,inflammatory bowel disease, autoimmune hemolytic anemia, autoimmunethyroiditis, cold and warm agglutinin diseases, Evans syndrome,hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP),sarcoidosis, Sjögren's syndrome, peripheral neuropathies (e.g.,Guillain-Barre syndrome), pemphigus vulgaris, and asthma.

The methods of treating Btk kinase-associated conditions may compriseadministering at least one compound of Formula (I) alone or incombination with each other and/or other suitable therapeutic agentsuseful in treating such conditions. Therapeutically-effective amounts ofat least one compound of Formula (I) and other suitable therapeuticagents for treating such conditions may be administered. Accordingly,“therapeutically effective amount” is also intended to include an amountof the combination of compounds claimed that is effective to treat Btkkinase-associated conditions. The combination of compounds is preferablya synergistic combination. Synergy, as described, for example, by Chouet al., Adv. Enzyme Regul., 22:27-55 (1984), occurs when the effect (inthis case, inhibition of Btk) of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. Synergy can be in terms of lower cytotoxicity, increasedanti-Btk effect, or some other beneficial effect of the combinationcompared with the individual components.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), 4-substituted imidazo[1,2-a]quinoxalines as disclosed in U.S.Pat. No. 4,200,750; Interleukin-10, glucocorticoids, salicylates, nitricoxide, and other immunosuppressants; nuclear translocation inhibitors,such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs(NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such asprednisone or dexamethasone; antiviral agents such as abacavir;antiproliferative agents such as methotrexate, leflunomide, FK506(tacrolimus, PROGRAF®); cytotoxic drugs such as azathiprine andcyclophosphamide; TNF-α inhibitors such as tenidap, anti-TNF antibodiesor soluble TNF receptor, and rapamycin (sirolimus or RAPAMUNE®) orderivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating Btkkinase-associated conditions, including IL-1, IL-6, IL-8, IFNγ andTNF-α-mediated conditions, as described above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Another embodiment provides the compounds of Formula (I) for use intherapy. In the present embodiment, the use in therapy may include theadministration of a therapeutically-effective amount of a compound ofFormula (I).

The present invention also provides the use of the compounds of Formula(I) for the manufacture of a medicament for the treatment or prophylaxisof an allergic disorder and/or autoimmune and/or inflammatory disease.In the present embodiment, the use for the manufacture of a medicamentmay include the administration of a therapeutically-effective amount ofa compound of Formula (I) for the treatment of prophylaxis of anallergic disorder and/or autoimmune and/or inflammatory disease.

The present invention also provides the use of the compounds of Formula(I) for the manufacture of a medicament for treatment of cancer. Thepresent embodiment may include the use for the manufacture of amedicament includes the administration of a therapeutically-effectiveamount of a compound of Formula (I) for the treatment of prophylaxis ofan allergic disorder and/or autoimmune and/or inflammatory disease.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula (I) and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th Edition (1985), which is incorporated herein by referencein its entirety.

The compounds of Formula (I) may be administered by any means suitablefor the condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; buccally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,Gantrez); and agents to control release such as polyacrylic copolymer(e.g., Carbopol 934). Lubricants, glidants, flavors, coloring agents andstabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The therapeutically-effective amount of a compound of the presentinvention may be determined by one of ordinary skill in the art, andincludes exemplary dosage amounts for a mammal of from about 0.05 to1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats, horses, and the like. Thus, when the term “patient” is usedherein, this term is intended to include all subjects, most preferablymammalian species, that are affected by mediation of Btk enzyme levels.

Examples of compounds of Formula (I) as specified in the “Examples”section below, have been tested in one or more of the assays describedbelow.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 10 nM or less, for example, from 0.001 to 10 nM, asmeasured by the human recombinant Btk enzyme assay. Preferably, thecompounds of Formula (I) inhibit Btk enzymes with IC₅₀ values of 2 nMand less, for example, from 0.001 to 2 nM. Other preferred compoundsinhibit Btk enzymes with IC₅₀ values of 1.0 nM and less, for example,from 0.001 to 1.0 nM.

In one embodiment, the compounds of Formula (I) have useful potency inthe inhibition of intracellular calcium flux in Ramos RA1 B cellsstimulated with anti-human IgM, with IC₅₀ values of 250 nM or less, forexample, from 0.1 to 250 nM. More preferably, the compounds of Formula(I) have potency in the inhibition of intracellular calcium flux inRamos RA1 B cells stimulated with anti-human IgM with IC₅₀ values of 160nM or less, for example, from 0.1 to 160 nM; and with IC₅₀ values of 100nM or less, for example, from 0.1 to 100 nM.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 2 nM or less, for example, from 0.001 to 2 nM, asmeasured by the Human Recombinant Btk enzyme assay, and inhibit theintracellular calcium flux in Ramos RA1 B cells stimulated withanti-human IgM, with IC₅₀ values of 500 nM or less, for example, from0.1 to 500 nM.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 2 nM or less, for example, from 0.001 to 2 nM, asmeasured by the Human Recombinant Btk enzyme assay, and inhibit theintracellular calcium flux in Ramos RA1 B cells stimulated withanti-human IgM, with IC₅₀ values of 150 nM or less, for example, from0.1 to 150 nM.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 2 nM or less, for example, from 0.001 to 2 nM, asmeasured by the Human Recombinant Btk enzyme assay, and inhibit theintracellular calcium flux in Ramos RA1 B cells stimulated withanti-human IgM, with IC₅₀ values of 60 nM or less, for example, from 0.1to 60 nM.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 1 nM and less, for example, from 0.001 to 1 nM, asmeasured by the Human Recombinant Btk enzyme assay, and inhibit theintracellular calcium flux in Ramos RA1 B cells stimulated withanti-human IgM, with IC₅₀ values of 500 nM or less, for example, from0.1 to 500 nM.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 1 nM and less, for example, from 0.001 to 1 nM, asmeasured by the Human Recombinant Btk enzyme assay, and inhibit theintracellular calcium flux in Ramos RA1 B cells stimulated withanti-human IgM, with IC₅₀ values of 150 nM or less, for example, from0.1 to 150 nM.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 1 nM or less, for example, from 0.001 to 1 nM, asmeasured by the Human Recombinant Btk enzyme assay, and inhibit theintracellular calcium flux in Ramos RA1 B cells stimulated withanti-human IgM, with IC₅₀ values of 60 nM or less, for example, from 0.1to 60 nM.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 0.5 nM and less, for example, from 0.001 to 0.5 nM, asmeasured by the Human Recombinant Btk enzyme assay, and inhibit theintracellular calcium flux in Ramos RA1 B cells stimulated withanti-human IgM, with IC₅₀ values of 500 nM or less, for example, from0.1 to 500 nM.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 0.5 nM and less, for example, from 0.001 to 0.5 nM, asmeasured by the Human Recombinant Btk enzyme assay, and inhibit theintracellular calcium flux in Ramos RA1 B cells stimulated withanti-human IgM, with IC₅₀ values of 150 nM or less, for example, from0.1 to 150 nM.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 0.5 nM or less, for example, from 0.001 to 0.5 nM, asmeasured by the Human Recombinant Btk enzyme assay, and inhibit theintracellular calcium flux in Ramos RA1 B cells stimulated withanti-human IgM, with IC₅₀ values of 60 nM or less, for example, from 0.1to 60 nM.

Methods of Preparation

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will be recognized by one skilled in the art of organic synthesisthat some functional groups present in intermediate compounds, or incompounds of Formula (I), may be unstable to, or otherwise unsuited for,some of the reaction conditions used to prepare them or to convert themto other intermediates or to compounds of Formula (I). In these cases,the functional groups may be protected by conversion to alternativefunctional groups which are more stable to or suitable for the reactionconditions to be employed. These protected functional group can then beconverted back to the original functional group at a later stage of thesynthesis. Examples are the protection of a carboxylic acid as acarboxylate ester, the protection of a primary or secondary amine as atert-butyloxycarbonyl (Boc) derivative or benzyloxycarbonyl (Cbz)derivative, or the protection of an indole nitrogen as a2-trimethylsilylethoxymethyl (SEM) derivative. The use of protectinggroups is well known in the literature; an authoritative accountdescribing the many alternatives to the trained practitioner is Wuts, P.et al., Greene's Protective Groups in Organic Synthesis, Fourth Edition,Wiley-Interscience (2006).

Compound 3, representing certain compounds of Formula (I), can beprepared using methods shown in Scheme 1.

A substituted indolecarboxamide compound 1, where Y is an appropriategroup such as Br, Cl, or trifluoromethanesulfonyloxy, can be reactedwith a boronic acid or boronic acid ester compound 2, where Arrepresents one of the groups A of Formula (I) in which the point ofattachment to the indole moiety is located on a benzene or pyridine ringof A, to provide a compound 3. This reaction may be performed by using asuitable base such as potassium carbonate, cesium carbonate ortripotassium phosphate, and a suitable catalyst such astetrakis(triphenylphosphine)palladium,1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride, or1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride, in asuitable solvent such as 1,4-dioxane, N,N-dimethylformamide ortetrahydrofuran, optionally with one or more suitable co-solvents suchas water or ethanol. Such coupling reactions are commonly known asSuzuki-Miyaura coupling reactions, and are well known in the chemicalliterature (see, for example, Heravi, M. et al., Tetrahedron, 68:9145(2012), and references cited therein).

Alternatively, a substituted indolecarboxamide compound 1 can beconverted to the corresponding boronic acid or boronic acid estercompound 4 using methods well known in the chemical literature (see, forexample, Ishiyama, T. et al., Tetrahedron, 57:9813 (2001), andreferences cited therein). Examples of such methods are the reaction ofa compound 1 with a reagent such as4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) or5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) in the presence of abase such as potassium acetate and a suitable catalyst such as1,1′-bis(diphenylphosphino) ferrocene palladium(II) chloride in asuitable solvent to provide a boronic acid ester compound 4.Alternatively, reaction of compound 1 where Y is Br with anorganometallic reagent such as butyllithium or isopropylmagnesiumchloride, followed by treatment with a boric acid ester such astrimethyl borate or tri-isopropyl borate, then followed by hydrolysis ofthe resulting boronic acid ester, can provide a boronic acid compound 4(R═H). Reaction of a compound 4 with a suitable compound 5, wherein Arrepresents one of the groups A of Formula (I) in which the point ofattachment to the indole moiety is located on a benzene or pyridine ringof A, and Y is an appropriate group such as Br, Cl, ortrifluoromethanesulfonyloxy, using the Suzuki-Miyaura coupling reactionas described above, can also provide a compound 3.

A compound 2 can be prepared from a compound 5 using the same methoddescribed for the preparation of a compound 4 from a compound 1.

Certain compounds of Formula (I), represented by 7, can be preparedusing methods illustrated in Scheme 2.

These methods involve reacting a compound 6 bearing a primary orsecondary amine (that is, where XH represents a group A of Formula (I)where Q₁ is replaced by NHR₇ or C(R₁₀)₂NHR₇, or where Q₂ is replaced byH) with an appropriate reagent Q-Z, where Q represents Q₂, an optionallysubstituted quinazoline-4-yl, or 4,6-dichloro-1,3,5-triazin-2-yl, or aprecursor to such a group, and Z represents a leaving group such as Clor OH, to provide a compound 7, where XQ represents one of the groups Aof Formula (I) resulting from such a reaction. Such reactions of aminesare well known in the literature. One example of such a reaction isacylation of the amine with a carboxylic acid chloride or a carboxylicacid anhydride, usually performed in a suitable solvent such astetrahydrofuran, ethyl acetate, acetonitrile, or dichloromethane,usually in the presence of a base such as triethylamine,diisopropylethylamine, pyridine, or an aqueous solution of an inorganicbase such as sodium hydroxide or potassium carbonate. Alternatively, asolvent such as pyridine can be used, in which case the solvent can alsoserve as a base.

Another example of a reaction shown in Scheme 2 is acylation of theamine of a compound 6 with a carboxylic acid using any of a number ofamide coupling reagents well known in the literature, for example,(benzotriazol-1-yloxy)tris(dimethylamino) phosphoniumhexafluorophosphate (also known as BOP or Castro's reagent),0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (also known as HATU), or a reagent such asN,N′-dicyclohexylcarbodiimide (also known as DCC) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (also knownas EDC) in the presence of a co-reagent such as 1-hydroxybenzotriazole(also known as HOBT) or 1-hydroxy-7-azabenzotriazole (also known asHOAT). Such reactions are usually performed in a suitable solvent suchas ethyl acetate, dichloromethane, tetrahydrofuran,N,N-dimethylformamide or N-methylpyrrolidine-2-one, in the presence of asuitable base such as triethylamine or diisopropylethylamine.

Another example of a reaction shown in Scheme 2, which can be used toprepare a compound 7 where Q is SO₂CH═CHR₁₀, is treatment of the amineof a compound 6 with an appropriate 2-chloroethanesulfonyl chloride, ina suitable solvent such as dichloromethane or tetrahydrofuran, in thepresence of a base such as triethylamine or diisopropylethylamine. Inthis case, an intermediate 2-chloroethanesulfonamide can be formed,which in the presence of base can undergo loss of HCl to provide thedesired ethenesulfonamide.

Another example of a reaction shown in Scheme 2, which can be used toprepare a compound 7 where Q is 4,6-dichloro-1,3,5-triazin-2-yl or anoptionally substituted quinazolin-4-yl, is the reaction of the amine ofa compound 6 with cyanuric chloride or an optionally substituted4-chloroquinazoline, respectively, in a suitable solvent such astetrahydrofuran, in the presence of a suitable base such as potassiumcarbonate.

Another example of a reaction shown in Scheme 2, which can be used toprepare a compound 7 where Q is CN, is the reaction of the amine of acompound 6 with cyanogen bromide in a suitable solvent, such asN,N-dimethylformamide, in the presence of a suitable base, such ascesium carbonate.

Certain compounds of Formula (I) can be prepared from certain othercompounds of Formula (I) using methods shown in Scheme 3.

A compound 8 where R represents an optionally substituted benzyl group(which is an example of a compound of Formula (I)) can be converted tothe corresponding hydroxy compound 9 (also an example of a compound ofFormula (I)) using methods well-known in the literature, for example, bytreatment with hydrogen in the presence of an appropriate catalyst suchas palladium on charcoal in a suitable solvent such as ethanol, or (whenR is p-methoxybenzyl) by treatment with a strong acid such astrifluoroacetic acid in an appropriate solvent. A compound 9 can befurther converted into another compound of Formula (I), represented by10, by treatment with an alkylating agent such as an optionallysubstituted alkyl bromide, alkyl chloride, alkyl iodide or alkylsulfonate ester, in a suitable solvent and in the presence of a suitablebase such as potassium carbonate.

Certain intermediate compounds 6 of Scheme 2 can be prepared usingmethods analogous to those shown in Scheme 1, as shown in Scheme 4.

Reaction of a compound 1 with a boronic acid ester or boronic acidcompound 11 (where XP is analogous to XH in Scheme 2; P can be either Hor a suitable amine protecting group such as, for example,tert-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz), which are wellknown in the literature as protecting groups for amines), using theSuzuki-Miyaura coupling as described above (Scheme 1), can provide thecorresponding compound 6 after removal of the protecting group P ifnecessary. If P in compound 11 represents H, compound 6 can be obtaineddirectly.

By analogy to the methods illustrated in Scheme 1, an alternative methodto prepare compound 6 of Scheme 2 is also shown in Scheme 4. Reaction ofa boronic acid ester or boronic acid compound 4 of Scheme 1 with acompound 12, where Y is a suitable leaving group such as Br, Cl ortrifluorosulfonyloxy, using the Suzuki-Miyaura coupling as describedabove, can also provide a compound 6. As described above, P can eitherbe H, or a suitable protecting group in which case deprotection canprovide the compound 6.

Also, a compound 11 can be prepared from a compound 12 using the samemethod described for the preparation of a compound 4 from a compound 1(Scheme 1).

Compounds 15, which are examples of compounds 6 of Scheme 2, can beprepared using methods shown in Scheme 5.

Reaction of a compound 1 with a vinylic boronic acid ester or boronicacid compound 13, where P is a suitable amine protecting group such asBoc or Cbz and m is 1 or 2, using the Suzuki-Miyaura reaction asdescribed above (see Scheme 1) can provide a compound 14. The doublebond of the dihydropyrrole (m=1) or tetrahydropiperidine (m=2) ring of14 can be reduced using methods well known in the literature, forexample, by treatment with hydrogen in the presence of a suitablecatalyst such as palladium adsorbed on charcoal, in a suitable solventsuch as methanol or ethanol, followed by removal of the protecting groupusing methods well known in the literature, to provide a compound 15.(If P represents a Cbz group, removal of the protecting group can beachieved in the same reaction as reduction of the double bond.)Alternatively, the order of the steps for the conversion of a compound14 to a compound 15 can be reversed: a protecting group P can be removedusing a suitable method, followed by hydrogenation of the double bond asdescribed.

Compounds 19, representing certain compounds 6 of Scheme 2, can beprepared as shown in Scheme 6.

Reaction of a compound 1 with a dehydrating agent such as phosphorusoxychloride, using methods well-known in the literature, can provide acompound 16. Treatment of a compound 16 with a suitable mono-protecteddiamine such as an aminopyrrolidine, an aminopiperidine, a piperazine,an octahydropyrrolopyrrole or an octahydropyrrolopyridine (representedby HN—X′—NP, 17, where can P represent a suitable protecting group suchas Cbz or Boc) can provide the corresponding compound 18. The conversionof a compound 16 to a compound 18 can be achieved using a suitablepalladium catalyst such as, for example, tris(dibenzylideneacetone)dipalladium, a ligand such as, for example,2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (also known as BINAP) or4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (also known asXantphos), and a base such as cesium carbonate or sodium tert-butoxide,in a suitable solvent such as 1,4-dioxane, toluene,N,N-dimethylacetamide or N-methylpyrrolidin-2-one. This reaction,commonly referred to as the Buchwald coupling, is well known in theliterature (see, for example, Surry, D. et al., Angew. Chem., 47:6338(2008), and references cited therein). The nitrile moiety of a compound18 can be hydrolyzed to the corresponding amide by treatment undersuitable conditions, for example, by heating with concentrated aqueoussulfuric acid, to provide a compound 19, which is an example of acompound 6 of Scheme 2. A protecting group P, if present in a compound18, can be removed during this reaction, or alternatively can be removedbefore or after the nitrile hydrolysis step using methods well-known inthe chemical literature.

It will be noted that in some cases a compound 18 or 19 can possess achiral center, for example, when 17 represents a protected3-aminopyrrolidine, 3-aminopiperidine, octahydropyrrolopyridine, ornon-symmetrical octahydropyrrolopyrrole. In these cases, a compound 18or 19 can be prepared in racemic form by using a racemic compound 17 inthe Buchwald coupling step. Alternatively, a compound 18 or 19 whichpossesses a chiral center can be prepared in enantiomerically pure orenantiomerically enriched form by using an enantiomerically pure orenantiomerically enriched compound 17 during the Buchwald coupling step.Alternatively, in cases where a chiral center is present, anenantiomerically pure or enantiomerically enriched compound 18 or 19 maybe prepared from a racemic compound 18 or 19, respectively, usingoptical resolution methods well known in the literature, for example, byselective crystallization of a diastereomeric salt formed with anenantiomerically pure or enantiomerically enriched acid, or bychromatography on a chiral stationary phase.

Compound 19, representing certain compounds 6 of Scheme 2, can also beprepared as shown in Scheme 7.

Conversion of a carboxylic acid 20 to an ester 21, such as a methylester (R═CH₃) or ethyl ester (R═C₂H₅), can be achieved using well-knownmethods, such as treatment with an acid catalyst such as sulfuric acidin a suitable alcoholic solvent such as methanol or ethanol. Using theBuchwald coupling procedure described for Scheme 6, a compound 21 can beconverted into a compound 22. The carboxylic acid ester of a compound 22can be converted to the corresponding amide, providing a compound 19(with removal of the protecting group P if appropriate), using wellknown methods, such as hydrolysis of the ester using a suitable basesuch as aqueous lithium hydroxide or sodium hydroxide, optionally in asuitable co-solvent such as methanol, ethanol or tetrahydrofuran. Theresulting carboxylic acid 22 (R═H) can then be converted into the amide19 using methods well known in the literature, for example, byconversion of the carboxylic acid to the corresponding acid chloride bytreatment with oxalyl chloride or thionyl chloride, followed bytreatment with ammonia; or by treatment of the carboxylic acid withammonia or ammonium chloride in the presence of a coupling reagent suchas dicyclohexylcarbodiimide, orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in thepresence of 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole.

Certain compounds 23 (which are examples of compounds 6 of Scheme 2) canbe prepared by a method shown in Scheme 8.

A compound 24 (where Z represents CN, which is an example of a compound18 of Scheme 6; or where Z represents a carboxylic acid ester, which isan example of a compound 22 of Scheme 7; and m and n are chosen to forman appropriate piperidine or pyrrolidine ring) can be converted into thecorresponding compound 25 using methods known in the literature, such asalkylation with an appropriate alkyl halide, or by treatment with anappropriate aldehyde or ketone followed by reduction of the intermediateiminium compound using a suitable reducing agent such as sodiumcyanoborohydride or sodium triacetoxyborohydride. The resulting compound25 can then be converted to the corresponding compound 23 usingappropriate methods: for example, if Z is CN, using the method describedfor the conversion of a compound 18 to a compound 19 (Scheme 6); or if Zis a carboxylic acid ester, using the method described for theconversion of a compound 22 to a compound 19 (Scheme 7).

Compounds 26, which are examples of compounds of Formula (I), can beprepared by a method shown in Scheme 9. A compound 27 (which can beprepared by installing a suitable protecting group such astrimethylsilylethoxymethyl on a compound 16 of Scheme 6) can be reactedwith a suitable organozinc compound such as 28, in the presence of acatalyst such as tetrakis(triphenylphosphine)palladium, to provide acompound 29. Such a palladium-catalyzed coupling of organozinccompounds, commonly known as the Negishi coupling, is well known in thechemical literature (see, for example, Negishi, E. et al.,Metal-Catalyzed Cross-Coupling Reactions, Second Edition, p. 815, deMeijere, A. et al., eds., Wiley-VCH (2004)). Removal of the protectinggroup of a compound 29 and reaction with an appropriate organostannanesuch as R₉Sn(CH₂CH₂CH₂CH₃)₃ in the presence of a catalyst such astetrakis (triphenylphosphine)palladium, can provide a compound 30. Sucha palladium-catalyzed coupling of organotin compounds, commonly known asthe Stille coupling, is well known in the chemical literature (see, forexample, Stille, J., Angew. Chem., Int. Ed. Engl., 25:508 (1986)).Conversion of the nitrile of a compound 30 to the carboxamide byhydrolysis, using methods described in Scheme 6 or related methods, canprovide a compound 26. In cases where R₈ is not H, R₈ can be present inthe organozinc reagent 28. Alternatively, a compound 29 where R₈ is Hcan be converted to the corresponding compound 29 where R₈ is alkylusing methods well-known in the literature, for example, by treatmentwith a suitable base such as potassium bis(trimethylsilyl)amide,followed by treatment with a suitable alkylating agent such as aniodoalkane.

Compounds 1 (see Scheme 1) used in the preparation of compounds ofFormula (I), and compounds 20 which can be used in the preparation ofcompounds 19 (see Scheme 7), can be prepared using procedures shown inScheme 10.

A substituted 2-aminobenzoic acid 31 (known in the literature, orprepared using procedures known in the literature) can be converted tothe corresponding 2-hydrazinylbenzoic acid 32 as the hydrochloric acidsalt using methods well known in the literature, for example, byconversion to the corresponding diazonium salt by treatment with sodiumnitrite in aqueous hydrochloric acid, followed by reduction with tin(II)chloride. Reaction of a compound 32 with a suitable ketone 33 such as2-butanone or acetone, in a suitable solvent with an appropriatecatalyst, for example, ethanol with hydrochloric acid, toluene withp-toluenesulfonic acid or trifluoroacetic acid, or acetic acid (in whichcase the solvent also can serve as the catalyst), can provide thecorresponding substituted indole 20. This reaction is commonly known asthe Fischer indole synthesis, and is well known in the chemicalliterature (see, for example, Hughes, D., Org. Prep. Proc. Int., 25:607(1993)). Alternatively, the Fischer indole synthesis can be carried outin two consecutive steps: a hydrazine 32 can react with the appropriateketone or aldehyde 33 under suitable conditions (such as in anappropriate solvent such as ethanol or toluene, optionally with asuitable catalyst such as p-toluenesulfonic acid) to form anintermediate hydrazone, which can be isolated and then reacted furtherunder suitable conditions (for example, ethanol with hydrochloric acid,acetic acid with zinc chloride, or toluene with trifluoroacetic acid) toprovide a compound 20. The carboxylic acid of a compound 20 can beconverted to the carboxamide of a compound 1 using methods described forthe conversion of a compound 22 (R═H) to a compound 19 in Scheme 7.

An alternative method for preparing a compound 1 is shown in Scheme 11.

A dibromonitrobenzene 34 can be treated with an appropriate vinylicorganomagnesium reagent 35 (Y′═Br or Cl) to provide a substituted indole36. This method, commonly called the Bartoli indole synthesis, is wellknown in the chemical literature (see, for example, Bartoli, G. et al.,Tetrahedron Lett., 30:2129 (1989), and Dobson, D. et al., Synlett, 79(1992)). A compound 36 can be converted into the corresponding compound37 (P═H, a compound 20 of Schemes 7 and 9) by treatment with a suitableorganolithium reagent such as n-butyllithium in a suitable solvent suchas tetrahydrofuran, followed by treatment with carbon dioxide, then withan aqueous acid to neutralize the intermediate carboxylate salt.Optionally, the indole nitrogen of a compound 36 can be protected usingmethods well known in the literature, for example, by alkylation with2-(trimethylsilyl)ethoxymethyl chloride to provide the corresponding2-trimethylsilylethoxymethyl (SEM) derivative, followed by conversion tothe corresponding carboxylic acid 37 (P=SEM) as described. Thecarboxylic acid of a compound 37 can then be converted to thecarboxamide of a compound 1, using methods described for thistransformation in Scheme 7. If the carboxamide so obtained is derivedfrom a compound 37 where P is a protecting group, deprotection usingsuitable methods known in the literature can then provide a compound 1.

As shown in Scheme 12, a compound 38 can be converted to a compound 39,which is an example of a compound 2 of Scheme 1. Analogously, a compound40 can be converted to a compound 41, which is an example of a compound5 of Scheme 1.

In Scheme 12, Y represents a suitable group such as Br, Cl ortrifluoromethanesulfonyloxy; (RO)₂B represents a boronic acid or boronicacid ester; and XH represents a group A of Formula (I) attached to theindole moiety of Formula (I) via a bond to a benzene or pyridine ring ofA but where Q₁ (if present) is replaced by NHR₇ or C(R₁₀)₂NHR₇ or Q₂ (ifpresent) is replaced by H; and Q represents a group Q₂, C(O)(C₁₋₄ alkylsubstituted with R₆), C(O)(C₃₋₆ cycloalkyl substituted with R₆),dichlorotriazinyl or quinazolin-4-yl substituted with R₆. Conversion ofa compound 38 to a compound 39, and conversion of a compound 40 to acompound 41, can be accomplished using the same methods described forthe analogous transformations of a compound 6 to a compound 7 in Scheme2. Also, conversion of a compound 38 to a compound 40, and conversion ofa compound 39 to a compound 41, can be accomplished using the methodsdescribed for the transformation of a compound 1 to a compound 4 inScheme 1.

Scheme 13 shows the preparation of compounds 42 and 43 (which areexamples of compounds 5 of Scheme 1) and of compounds 44 and 45 (whichare examples of compounds 2 of Scheme 1).

An isatoic anhydride 46 (where R′ and R″ represent optional substituentsselected from F, Cl, CH₃, CN and OCH₃) can react with a substitutedaniline 47 to produce an amide 48. Such reactions can be carried outunder a variety of conditions, for example, by heating in a suitablesolvent, or by heating in the presence of a reagent such astrimethylaluminum. A compound 48 can be converted into a substitutedquinazolinedione 42, for example, by treatment in a suitable solventwith phosgene or bis(trichloromethyl) carbonate (triphosgene).Optionally, a compound 42 can be converted to the corresponding compound44 using methods described for the conversion of a compound 1 to acompound 4 in Scheme 1. Alternatively, a compound 42 can optionally beconverted into a compound 43 using methods known well known in thechemical literature, for example, by treatment with an alkylating agentsuch as iodomethane in the presence of a suitable base such as cesiumcarbonate. A compound 43 can then be converted into the correspondingcompound 45 using the same methods described above. A compound 44 canalso be optionally converted into the corresponding compound 45 bymethods similar to those described for the conversion of a compound 42into a compound 43.

If R₅ of a compound 42, 43, 44 or 45 is other than hydrogen, a compound42, 43, 44 or 45 displays chirality, called atropisomerism, due tohindered rotation about the single bond connecting the substitutedphenyl ring to the quinazolinedione moiety, and exists as twoenantiomers. These enantiomeric atropisomers can be isolated as separatecompounds which are stable to interconversion under normal storageconditions. If desired, a compound 42, 43, 44 or 45 can be resolved intoseparate enantiomeric atropisomers, for example, by chromatography on achiral stationary phase. A separated enantiomeric atropisomer of acompound 42 or a compound 43 can then optionally be converted into astable enantiomeric atropisomer of a compound 44 or a compound 45,respectively, as described above.

An alternative synthesis of a compound 48 of Scheme 13 is shown inScheme 14. A substituted 2-nitrobenzoic acid 49 can be converted to acompound 50 using well-known amide bond forming reactions, for example,by conversion of a compound 49 to the corresponding carboxylic acidchloride and reaction with a substituted aniline 47, or by directreaction of a compound 49 and a compound 47 in the presence of asuitable coupling reagent suchO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), or a mixture of1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (EDC) and1-hydroxybenzotriazole hydrate (HOBT), using methods well known in theliterature. The nitro group of a compound 50 can then be reduced, usingone of a wide variety of methods known in the literature, to give acompound 48.

Other examples of compounds 2 and 5 of Scheme 1, and of compounds 11 and12 of Scheme 4, are known in the literature, or can be prepared usingmethods known in the literature. For example, U.S. Pat. No. 8,084,620describes the preparation of a number of such compounds useful in thepreparation of compounds of Formula (I).

Certain compounds of Formula (I) may exhibit hindered rotation about thebond joining the group A to the indole ring. In some cases, the hinderedrotation may be such that two isomers about this bond, known asatropisomers, can be isolated as separate compounds which are stable tointerconversion under common storage and handling conditions. Caseswhere this hindered rotation may be observed are cases where R₃ is nothydrogen and where A is a substituted benzene or pyridine ring bearing asubstituent R₅ which is also not hydrogen, or where R₃ is not hydrogenand where A is, for example, a substituted1,2,3,4-tetrahydroisoquinolin-5-yl, a substituted1,2,3,4-tetrahydroisoquinolin-8-yl, a substituted1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl, a substitutedisoindolin-4-yl, a substituted 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl,a substituted 3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl, a substitutedindolin-4-yl, or a substituted2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl group. In these cases, thecompounds of Formula (I) may be prepared in racemic or scalemic form,and the two atropisomers may be separated using methods known in theliterature, for example, by chromatography on a chiral stationary phase.

Likewise, a compound 6 of Schemes 2 and 4 may also exhibit hinderedrotation about the bond joining the group XH to the indole ring, and canbe isolated as separate compounds which are stable to interconversionunder common storage and handling conditions. Cases where this hinderedrotation may be observed are cases where R₃ is not hydrogen and where XHis a substituted benzene or pyridine ring bearing a substituent R₅ whichis also not hydrogen, or where R₃ is not hydrogen and where XH is, forexample, an optionally substituted 1,2,3,4-tetrahydroisoquinolin-5-yl,an optionally substituted 1,2,3,4-tetrahydroisoquinolin-8-yl, anoptionally substituted1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl, an optionallysubstituted isoindolin-4-yl, an optionally substituted3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl, an optionally substituted3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl, an optionally substitutedindolin-4-yl, or an optionally substituted2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl group. In these cases, thecompound 6 can be prepared in racemic or scalemic form as shown inScheme 4, and the two atropisomers of 6 may be separated using methodsknown in the literature, for example, by chromatography on a chiralstationary phase. A separated enantiomeric atropisomer can then beconverted into a single enantiomer of a compound 7, which representscertain compounds of Formula (I), as shown in Scheme 2.

In some cases, when the conversion of an intermediate compound intoanother intermediate compound or a compound of Formula (I) requires morethan one synthetic reaction, the order of the individual steps can bechanged. One example is shown in Scheme 12. Conversion of a compound 38to a compound 41 can be done by (1) conversion of the amine of thecompound 38 to the substituted amine of a compound 39, followed by (2)conversion of the group Y of the compound 39 to the boronic acid orboronic acid ester of the compound 41. Alternatively, the sameconversion of a compound 38 to a compound 41 can be done by (1)conversion of the group Y of the compound 38 to the boronic acid orboronic acid ester of a compound 40, followed by (2) conversion of theamine of the compound 40 to the substituted amine of the compound 41.Such cases will be recognized by one skilled in the art of organicsynthesis.

EXAMPLES

Compounds of the current invention, and intermediates used in thepreparation of compounds of the current invention, can be prepared usingprocedures shown in the following Examples and related procedures. Themethods and conditions used in these Examples, and the actual compoundsprepared in these Examples, are not meant to be limiting, but are meantto demonstrate how the compounds of the current invention can beprepared. Starting materials and reagents used in these Examples, whennot prepared by a procedure described herein, are generally eithercommercially available, or are reported in the chemical literature, ormay be prepared by using procedures described in the chemicalliterature. The invention is further defined in the following Examples.It should be understood that the Examples are given by way ofillustration only. From the above discussion and the Examples, oneskilled in the art can ascertain the essential characteristics of theinvention, and without departing from the spirit and scope thereof, canmake various changes and modifications to adapt the invention to varioususes and conditions. As a result, the invention is not limited by theillustrative examples set forth herein below, but rather defined by theclaims appended hereto.

In the examples given, the phrase “dried and concentrated” generallyrefers to removal of most residual water from a solution in an organicsolvent using either anhydrous sodium sulfate or magnesium sulfate,followed by filtration and removal of the solvent from the filtrate(generally under reduced pressure and at a temperature suitable to thestability of the material being prepared). Column chromatography wasgenerally performed using the flash chromatography technique (Still, W.et al., J. Org. Chem., 43:2923 (1978)), or with pre-packed silica gelcartridges using an Isco medium pressure chromatography apparatus(Teledyne Corporation), eluting with the solvent or solvent mixtureindicated. Preparative high pressure liquid chromatography (HPLC) wasperformed using a reverse-phase column (Waters SunFire Cis, WatersXBridge Cis, PHENOMENEX® Axia C₁₈, YMC S5 ODS or the like) of a sizeappropriate to the quantity of material being separated, generallyeluting with a gradient of increasing concentration of methanol oracetonitrile in water, also containing 0.05% or 0.1% trifluoroaceticacid or 10 mM ammonium acetate, at a rate of elution suitable to thecolumn size and separation to be achieved. Supercritical fluidchromatography (SFC), a form of normal phase HPLC using a mobile phasecontaining super- or subcritical fluid CO₂ and polar organic modifierssuch as alcohols, was used to separate chiral compounds (White, C. etal., J. Chromatography A, 1074:175 (2005)). Chiral SFC separation ofenantiomers or diastereomers was performed using conditions describedfor the individual cases. Mass spectral data were obtained by liquidchromatography-mass spectrometry using electrospray ionization. Chemicalnames were determined using CHEMDRAW® Ultra, version 9.0.5(CambridgeSoft). The following abbreviations are used:

-   AcCN acetonitrile-   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   BOP benzotriazol-1-yloxy)tris(dimethylamino)phosphonium    hexafluorophosphate-   DCM dichloromethane-   DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone-   DIEA diisopropylethylamine-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   EDC 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride-   EtOAc ethyl acetate-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HOBT 1-hydroxybenzotriazole hydrate-   MeCN acetonitrile-   MeOH methanol-   min minute(s)-   NBS N-bromosuccinimide-   PdCl₂(dppf)    1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Pd₂(dba)₃ tris-(dibenzylideneacetone)dipalladium-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   HPLC high pressure liquid chromatography-   g gram(s)-   mL milliliter(s)-   μL microliter(s)-   mmol millimole(s)

Intermediate 1 4-Bromo-2,3-dimethyl-1H-indole-7-carboxamide

Intermediate 1A: 4-Bromo-2,3-dimethyl-1H-indole-7-carboxylicacid

A suspension of 4-bromo-2-hydrazinylbenzoic acid hydrochloride [preparedaccording to U.S. Pat. No. 8,084,620, Intermediate 46-1, Step 1] (5.87g, 21.9 mmol) in acetic acid (73 mL) at 75° C. was treated with2-butanone (9.8 mL, 110 mmol). The mixture was heated on an oil bath at110° C. After 18 h, the mixture was concentrated under vacuum to providea dark brown solid. The residue was suspended in EtOAc and the insolublematerial was collected by filtration, washed with EtOAc and air dried.The filtrates were concentrated and the residue was again suspended inEtOAc. Additional solid was collected by filtration, washed with EtOAcand air dried. The two solids were combined to provide4-bromo-2,3-dimethyl-1H-indole-7-carboxylic acid as a brown solid (4.63g, 79% yield). LCMS (M+H)⁺ m/z 268, 270. ¹H NMR (400 MHz, DMSO-d₆) δ13.29-12.97 (m, 1H), 10.87 (br. s., 1H), 7.48 (d, J=7.9 Hz, 1H), 7.20(d, J=8.1 Hz, 2H), 2.40 (s, 3H), 2.36 (s, 3H).

Intermediate 1

A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxylic acid (4.63 g,17.3 mmol), EDC (4.97 g, 25.9 mmol) and HOBT (3.44 g, 22.5 mmol) in THF(276 mL) and DCM (69 mL) was stirred at room temperature for 1 h, thentreated with 28% aqueous ammonium hydroxide (5.38 mL, 138 mmol). Theresulting suspension was stirred at room temperature for 4 days. Themixture was concentrated and the residue was partitioned between waterand EtOAc. The layers were separated and the aqueous phase was extractedagain with EtOAc. The combined organic layers were washed with brine,dried and concentrated to provide4-bromo-2,3-dimethyl-1H-indole-7-carboxamide as a yellow solid (3.34 g,72% yield). Mass spectrum m/z 267, 269 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 10.92 (s, 1H), 8.01 (br. s., 1H), 7.48-7.31 (m, 2H), 7.14 (d, J=7.9Hz, 1H), 2.39 (d, J=0.4 Hz, 3H), 2.34 (s, 3H).

Intermediate 2 4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Intermediate 2A: 4-Bromo-2,5-difluorobenzoic acid

A solution of 1,4-dibromo-2,5-difluorobenzene (640 mg, 2.35 mmol) in drydiethyl ether (10 mL) cooled in a dry ice-acetone bath was treateddropwise with 2.5 M n-butyllithium in hexanes (1.04 mL, 2.59 mmol). Theresulting solution was stirred at −78° C. for 30 min, then was treatedwith a piece of dry ice. The cooling bath was removed after 5 min andthe mixture was stirred for another 30 min while warming to roomtemperature. The mixture was diluted with EtOAc and water. The organicphase was separated and washed twice with saturated aqueous NaHCO₃. Thecombined aqueous phases were acidified with 1 M aqueous HCl, extractedtwice with DCM, and the combined organic phases were dried andconcentrated to give 4-bromo-2,5-difluorobenzoic acid as a white solid(297 mg, 53% yield).

Intermediate 2B: 4-Bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride

A mixture of 4-bromo-2,5-difluorobenzoic acid (2.50 g, 10.6 mmol) andhydrazine (3.81 mL, 121 mmol) in N-methyl-2-pyrrolidinone (2 mL) washeated at 95° C. for 4 h. The cooled mixture was poured into vigorouslystirred 6 M aqueous HCl (400 mL) which was cooled in an NaCl-ice bath.The resulting precipitate was collected by filtration, washed with 6 Maqueous HCl (200 mL) and dried under vacuum to give4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride as a yellowsolid (1.88 g, 71% purity, 44% yield), used without furtherpurification.

Alternative Synthesis of 4-Bromo-5-fluoro-2-hydrazinylbenzoic acidhydrochloride

A suspension of 2-amino-4-bromo-5-fluorobenzoic acid (10.0 g, 42.7 mmol)in a mixture of 37% aqueous HCl (42.7 mL) and water (14.3 mL), cooledwith an NaCl-ice bath, was treated dropwise with a solution of sodiumnitrite (3.24 g, 47.0 mmol) in water (15.7 mL). When addition wascomplete, the mixture was stirred for 30 min more. A solution of tin(II)chloride dihydrate (28.9 g, 128 mmol) in 37% aqueous HCl (27.5 mL) wasadded dropwise. The cooling bath was removed and the mixture was stirredat room temperature for 45 min. The thick suspension was filtered andthe collected precipitate was washed thoroughly with water and driedovernight under reduced pressure. The collected solid was trituratedwith MeOH with sonication, and the precipitate was collected byfiltration, washed with MeOH and dried. The filtrate was concentrated,and the residue was triturated with DCM. The resulting precipitate wascollected by filtration and dried, and the two batches of precipitatewere combined to give 4-bromo-5-fluoro-2-hydrazinylbenzoic acidhydrochloride as a white solid (5.37 g, 44% yield). Mass spectrum m/z249, 251 (M+H)⁺.

Intermediate 2C:4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylicacid

A stirred suspension of 4-bromo-5-fluoro-2-hydrazinylbenzoic acidhydrochloride (1.00 g, 3.50 mmol) in acetic acid (11.7 mL) was treatedwith 2-butanone (1.26 mL, 14.0 mmol) at room temperature. The mixturewas heated at 75° C. for 30 min, forming a brown solution, then wasfurther heated at 110° C. After 16 h the mixture was concentrated, andthe residue was suspended in EtOAc. The precipitate was collected byfiltration, washed with EtOAc and air dried. The filtrates wereconcentrated and the residue was suspended in EtOAc, forming additionalprecipitate which was collected by filtration, washed with EtOAc and airdried. The two collected precipitates were combined to provide4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid as a brownsolid (0.515 g, 51% yield). Mass spectrum m/z 286,288 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 13.84-12.75 (m, 1H), 10.96 (s, 1H), 7.45 (d, J=9.7Hz, 1H), 2.40 (s, 3H), 2.37 (s, 3H).

Intermediate 2

Following the procedure used in the final step of the preparation ofIntermediate 1, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylicacid was converted into4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide in 75% yield. Massspectrum m/z 285, 287 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),8.08 (br. s., 1H), 7.62-7.44 (m, 2H), 2.39 (s, 3H), 2.35 (s, 3H).

Intermediate 3 4-Bromo-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide

Intermediate 3A: 4-Bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride

Following the alternative procedure used for of the preparation of4-bromo-5-fluoro-2-hydrazinylbenzoic acid HCl salt [Intermediate 2B],2-amino-4-bromo-5-chlorobenzoic acid was converted into4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride in 39% yield.Mass spectrum m/z 265, 267, 269 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82(b, 1H), 7.86 (s, 1H), 7.58 (s, 1H).

Intermediate 3B:4-Bromo-2-(2-(butan-2-ylidene)hydrazinyl)-5-chlorobenzoicacid

A stirred suspension of 4-bromo-5-chloro-2-hydrazinylbenzoic acidhydrochloride (1.50 g, 4.97 mmol) in acetic acid (16.6 mL) was treatedat room temperature with 2-butanone (1.34 mL, 14.9 mmol). The mixturewas heated on an oil bath to 75° C. for 30 min, then was heated at 110°C. After 16 h the mixture was concentrated under vacuum and the residuewas suspended in EtOAc. The precipitate was collected by filtration,washed with EtOAc and air dried to provide4-bromo-2-(2-(butan-2-ylidene)hydrazinyl)-5-chlorobenzoic acid as ayellow solid (0.574 g, 36% yield). Mass spectrum m/z 319, 321, 323(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 13.59 (br. s., 1H), 10.66 (s, 1H),7.89 (s, 1H), 7.82 (s, 1H), 2.33 (q, J=7.5 Hz, 2H), 1.89 (s, 3H), 1.09(t, J=7.4 Hz, 3H).

Intermediate 3C:4-Bromo-5-chloro-2,3-dimethyl-1H-indole-7-carboxylicacid

A mixture of 4-bromo-2-(2-(butan-2-ylidene)hydrazinyl)-5-chlorobenzoicacid (0.574 g, 1.80 mmol) and TFA (1.11 mL, 14.4 mmol) in toluene (4.6mL) was heated at 90° C. After 21 h, the mixture was concentrated undervacuum and the residue was suspended in EtOAc. The precipitate wascollected by filtration, washed with EtOAc and air dried to provide4-bromo-5-chloro-2,3-dimethyl-1H-indole-7-carboxylic acid as adark-colored solid (0.373 g, 69% yield). Mass spectrum m/z 302, 304, 306(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 13.40 (br. s., 1H), 11.06 (s, 1H),7.67 (s, 1H), 2.40 (s, 3H), 2.37 (s, 3H).

Intermediate 3

Following the procedure used in the final step of the preparation ofIntermediate 1, 4-bromo-5-chloro-2,3-dimethyl-1H-indole-7-carboxylicacid was converted into4-bromo-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide in 82% yield. Massspectrum m/z 301, 303, 305 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 8.13 (br. s., 1H), 7.76 (s, 1H), 7.51 (br. s., 1H), 2.40 (s, 3H),2.36 (s, 3H).

Intermediate 4 4-Bromo-3-methyl-1H-indole-7-carboxamide

Intermediate 4A: 4,7-Dibromo-3-methyl-1H-indole

A solution of 1,4-dibromo-2-nitrobenzene (4.60 g, 16.4 mmol) in THF (66mL) cooled at −78° C. was treated over 10 min with 0.5 M(E)-prop-1-enylmagnesium bromide in THF (98.2 mL, 49.1 mmol). Theresulting mixture was stirred at −78° C. for 2 h, then at roomtemperature for 2 h. The mixture was treated with saturated aqueousNH₄Cl (100 mL), then with water and 1 M aqueous HCl (to pH about 1-2),then was extracted with EtOAc. The organic phase was washed with brine,dried and concentrated. The residue was subjected to columnchromatography on silica gel (120 g), eluting with EtOAc-hexanes(gradient from 5-25%), to provide 4,7-dibromo-3-methyl-1H-indole (1.75g, 37% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (1H, br. s.), 7.16 (2H,s), 7.09 (1H, s), 2.57 (3H, d, J=1.1 Hz).

Intermediate 4B:4,7-Dibromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

A suspension of sodium hydride (60% in mineral oil, 0.254 g, 6.36 mmol)in THF (18.4 mL), cooled at 0° C., was treated portionwise with asolution of 4,7-dibromo-3-methyl-1H-indole (1.75 g, 6.06 mmol) in THF(1.8 mL), then with 2-(trimethylsilyl) ethoxymethyl chloride (1.19 mL,6.06 mmol). The mixture became a light yellow solution which was stirredat room temperature for 3 h. The mixture was then treated with water andextracted with EtOAc. The organic phase was washed with brine, dried andconcentrated. The residue was subjected to column chromatography onsilica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-5%), toprovide4,7-dibromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole as alight yellow oil (2.4 g, 95% yield). Mass spectrum m/z 417, 419, 421(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.16 (m, 1H), 7.14-7.09 (m, 1H),6.99 (d, J=0.9 Hz, 1H), 5.79 (s, 2H), 3.50 (dd, J=8.6, 7.7 Hz, 2H), 2.53(d, J=0.9 Hz, 3H), 0.92-0.86 (m, 2H),−0.04 (s, 9H).

Intermediate 4C:4-Bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid

A solution of4,7-dibromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(2.30 g, 5.49 mmol) in THF (27.4 mL) at −78° C. was treated with 2.5 Mn-butyllithium in hexanes (2.33 mL, 5.82 mmol). The mixture was stirredat −78° C. for 10 min, then was bubbled with carbon dioxide for 15 min.The mixture was then warmed to room temperature, stirred for 4 h, andtreated with water. The pH was adjusted to 2-3 with 1 M aqueous HCl andthe mixture was extracted with EtOAc. The organic phase was washed withbrine, dried and concentrated to provide crude4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid as a brown oil (2.0 g, 95% yield), used without furtherpurification.

Intermediate 4D:4-Bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

Following the procedure used in the final step of the preparation ofIntermediate 1,4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid was converted into4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamidein 36% yield. Mass spectrum m/z 405, 407 (M+Na)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 7.91 (s, 1H), 7.47 (s, 1H), 7.37 (d, J=0.9 Hz, 1H), 7.26 (d,J=7.7 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 5.57 (s, 2H), 3.25 (dd, J=8.7,7.6 Hz, 2H), 2.47 (d, J=0.9 Hz, 3H), 0.77-0.71 (m, 2H),−0.09 (s, 9H).

Intermediate 4

A solution of4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(0.72 g, 1.88 mmol), 1.0 M tetra-n-butylammonium fluoride in THF (5.63mL, 5.63 mmol) and ethylenediamine (0.761 mL, 11.3 mmol) in DMF (9.4 mL)was heated at 45° C. for 4 days. Additional tetra-n-butylammoniumfluoride (2 mL) was added and the mixture was heated at 50° C. After 5days, additional ethylenediamine (4.0 mL) was added and the mixture washeated at 70° C. for 5 h. The mixture was cooled to room temperature,treated with water and 1 M aqueous HCl and extracted with EtOAc. Theorganic phase was washed sequentially with saturated aqueous NaHCO₃ andbrine, dried and concentrated. The residue was subjected to columnchromatography on silica gel (24 g), eluting with EtOAc-hexanes(gradient from 30-60%), to provide4-bromo-3-methyl-1H-indole-7-carboxamide as an off-white solid (0.35 g,74% yield). Mass spectrum m/z 253, 255 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ10.24 (br. s., 1H), 7.32-7.29 (m, 3H), 7.22-7.18 (m, 1H), 7.15 (d, J=1.1Hz, 1H), 2.60 (d, J=1.1 Hz, 3H).

Intermediate 5 4-Bromo-2-methyl-1H-indole-7-carboxamide

4-Bromo-2-methyl-1H-indole-7-carboxamide was prepared following theprocedures used to prepare Intermediate 4 but substitutingprop-1-en-2-ylmagnesium chloride for (E)-prop-1-enylmagnesium chloride.¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (br. s., 1H), 8.04 (br. s., 1H), 7.49(d, J=8.1 Hz, 1H), 7.40 (br. s., 1H), 7.20 (d, J=8.1 Hz, 1H), 6.16 (dd,J=2.2, 0.9 Hz, 1H), 2.44 (d, J=0.4 Hz, 3H).

Intermediate 6 4-Bromo-1H-indole-7-carboxamide

Intermediate 6A: 4,7-Dibromo-1H-indole

Following the procedure used in the preparation of Intermediate 4A butsubstituting vinylmagnesium bromide for (E)-prop-1-enylmagnesiumbromide, 1,4-dibromo-2-nitrobenzene was converted into4,7-dibromo-1H-indole as a brown oil in 47% yield. ¹H NMR (400 MHz,DMSO-d₆) δ 11.73 (br. s., 1H), 7.54 (t, J=2.9 Hz, 1H), 7.30-7.24 (m,1H), 7.22-7.16 (m, 1H), 6.53 (dd, J=3.1, 2.0 Hz, 1H).

Intermediate 6B: 4-Bromo-1H-indole-7-carboxylic acid

Following the procedure used in the preparation of Intermediate 4C,4,7-dibromo-1H-indole was converted into 4-bromo-1H-indole-7-carboxylicacid in 82% yield. Mass spectrum m/z 238, 240 (M−H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 13.22 (br. s., 1H), 11.41 (br. s., 1H), 7.66 (d, J=8.1 Hz,1H), 7.49-7.47 (m, 1H), 7.35 (d, J=7.9 Hz, 1H), 6.52 (dd, J=3.1, 2.2 Hz,1H).

Intermediate 6

Following the procedure used in the final step of the preparation ofIntermediate 1, 4-bromo-1H-indole-7-carboxylic acid was converted into4-bromo-1H-indole-7-carboxamide in 71% yield. Mass spectrum m/z 239, 241(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.44 (br. s., 1H), 8.11 (br. s.,1H), 7.62 (d, J=7.9 Hz, 1H), 7.49-7.41 (m, 2H), 7.30 (d, J=7.9 Hz, 1H),6.45 (dd, J=3.1, 2.0 Hz, 1H).

Intermediate 74-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

Following the procedures used in steps B through D of the preparation ofIntermediate 4, 4,7-dibromo-1H-indole (Intermediate 6A) was convertedinto4-bromo-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indole-7-carboxamide asa solid. Mass spectrum m/z 369, 371 (M+H)⁺, 391, 393 (M+Na)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.64 (d, J=3.3 Hz, 1H), 7.50 (s, 1H),7.33 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H), 6.53 (d, J=3.3 Hz, 1H),5.68 (s, 2H), 3.30 (s, 2H), 3.29-3.24 (m, 2H), 0.82-0.69 (m, 2H),−0.09(s, 9H).

Intermediate 84-Bromo-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole-7-carboxamide

Intermediate 8A: 2,5-Dibromo-1-fluoro-3-nitrobenzene

A mixture of copper(II) bromide (0.713 g, 3.19 mmol) and tert-butylnitrite (0.556 mL, 4.68 mmol) in acetonitrile (5.67 mL) was heated at60° C. for 10 min, then was treated dropwise with a solution of4-bromo-2-fluoro-6-nitroaniline (0.500 g, 2.13 mmol) in acetonitrile(8.51 mL). The mixture was stirred at 60° C. for 30 min, then was cooledto room temperature, treated with 1 M aqueous HCl and extracted withEtOAc. The organic phase was washed sequentially with saturated aqueousNaHCO₃ and brine, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (40 g), eluting with EtOAc-hexanes(5%), to provide 2,5-dibromo-1-fluoro-3-nitrobenzene as an off-whitesolid (0.534 g, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (t, J=2.0Hz, 1H), 8.15 (dd, J=8.4, 2.2 Hz, 1H).

Intermediate 8B: 2,5-Dibromo-1-((4-methoxybenzyl)oxy)-3-nitrobenzene

A suspension of sodium hydride (60% in mineral oil, 0.637 g, 15.9 mmol)in THF (76 mL) was treated with (4-methoxyphenyl)methanol (1.89 g, 13.7mmol) and stirred at room temperature for 30 min. The mixture wastreated with 2,5-dibromo-1-fluoro-3-nitrobenzene (3.40 g, 11.4 mmol) andstirred at room temperature for 4 h. Water and saturated aqueous NH₄Clwere added and the mixture was extracted with EtOAc. The organic phasewas washed with brine, dried and concentrated. The residue wascrystallized from EtOAc-hexanes to provide a yellow solid (0.879 g). Thefiltrate from collection of the solid was concentrated and subjected tocolumn chromatography on silica gel (80 g), eluting with EtOAc-hexanes(step gradient from 5-20%) to provide, after crystallization fromEtOAc-hexanes, additional yellow solid (0.536 g). The filtrate wascombined with additional impure material recovered from thechromatography column effluent, and crystallization was repeated threetimes, yielding additional yellow solids. All solids were combined toprovide 2,5-dibromo-1-((4-methoxybenzyl)oxy)-3-nitrobenzene (2.28 g,48%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (d, J=2.0 Hz, 1H), 7.74 (d, J=2.2Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 5.26 (s, 2H),3.78 (s, 3H).

Intermediate 8C:4,7-Dibromo-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole

Following the procedure used to prepare Intermediate 4A, butsubstituting (E)-but-2-en-2-ylmagnesium bromide for(E)-prop-1-enylmagnesium bromide,2,5-dibromo-1-((4-methoxybenzyl)oxy)-3-nitrobenzene was converted into4,7-dibromo-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole in 44%yield. Mass spectrum m/z 438, 440, 442 (M−H)⁺.

Intermediate 8

Following the procedures used to convert Intermediate 4B to Intermediate4D, 4,7-dibromo-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole wasconverted into4-bromo-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole-7-carboxamide.Mass spectrum m/z 403, 405 (M−H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s,1H), 7.71 (br. s., 1H), 7.59 (br. s., 1H), 7.45 (d, J=8.6 Hz, 2H), 7.14(s, 1H), 6.97 (d, J=8.6 Hz, 2H), 5.22 (s, 2H), 3.77 (s, 3H), 2.35 (s,3H), 2.30 (s, 3H).

Intermediate 92,3-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide

A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate1](0.79 g, 2.96 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.751 g,2.96 mmol), potassium acetate (0.581 g, 5.91 mmol), and PdCl₂(dppf) DCMadduct (0.121 g, 0.148 mmol) in 1,4-dioxane (9.9 mL) was bubbled withnitrogen for 2-3 min, then was heated at reflux under nitrogen. After 16h, the mixture was cooled to room temperature, filtered through CELITE®,and the solids were washed with a mixture of THF and EtOAc. The combinedfiltrates were concentrated and the residue was subjected to columnchromatography on silica gel (24 g), eluting with EtOAc-hexanes(gradient from 20-40%), to provide2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamideas a yellow glassy solid (0.798 g, 69% yield). Mass spectrum m/z 315(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.01 (br. s., 1H), 7.48 (d, J=7.5 Hz,1H), 7.27 (d, J=7.7 Hz, 1H), 5.88 (br. s., 2H), 2.43 (s, 3H), 2.39 (d,J=0.4 Hz, 3H), 1.44 (s, 12H).

Intermediate 102-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide

Following the procedure used in the preparation of Intermediate 9,4-bromo-2-methyl-1H-indole-7-carboxamide [Intermediate 5] was convertedinto2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamidein 68% yield. Mass spectrum m/z 301 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ10.82 (br. s., 1H), 8.03 (br. s., 1H), 7.53 (d, J=7.7 Hz, 1H), 7.37 (br.s., 1H), 7.33 (d, J=7.5 Hz, 1H), 6.50 (dd, J=2.2, 0.9 Hz, 1H), 2.44 (d,J=0.7 Hz, 3H), 1.33 (s, 12H).

Intermediate 11 4-Bromo-2,3-dimethyl-1H-indole-7-carbonitrile

A suspension of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide[Intermediate 1](5.65 g, 21.2 mmol) in THF (151 mL) was treated slowlywith phosphorus oxychloride (13.8 mL, 148 mmol). The resulting mixturewas stirred at room temperature for 23 h, then was concentrated. Theresidue was suspended in EtOAc and the precipitate was collected byfiltration, washed sequentially with water, saturated aqueous NaHCO₃ andagain with water, and air dried. The organic filtrate was concentrated,and the residue was suspended in water. The resulting precipitate wascollected by filtration, washed sequentially with water, saturatedaqueous NaHCO₃ and again with water, and air dried. The two precipitatestogether provided 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile as ayellow solid (4.68 g, 89% yield). Mass spectrum m/z 249, 251 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 11.89 (br. s., 1H), 7.35 (d, J=7.9 Hz, 1H),7.26 (d, J=7.9 Hz, 1H), 2.39 (s, 3H), 2.34 (s, 3H).

Intermediate 12 4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

Following the procedure used to prepare Intermediate 11,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 2]was converted into4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile in 56% yield.Mass spectrum m/z 267, 269 (M+H)⁺.

Intermediate 13(S)-4-(3-Aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide

Intermediate 13A: (S)-Benzyl(1-(7-cyano-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl) carbamate

A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate11](2.50 g, 10.0 mmol), (S)-benzyl piperidin-3-ylcarbamate (2.47 g, 10.5mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.312 g, 0.502mmol), tris(dibenzylideneacetone)dipalladium (0.460 g, 0.502 mmol) andCs₂CO₃ (4.58 g, 14.1 mmol) in 1,4-dioxane (143 mL) was bubbled withnitrogen, then heated at 100° C. After 16 h, the mixture was cooled toroom temperature, diluted with THF, filtered through CELITE®, and thesolids were washed with THF. The combined filtrates were concentratedand the residue was subjected to chromatography on silica gel (80 g),eluting with EtOAc-hexanes (gradient from 15-30%), to provide (S)-benzyl(1-(7-cyano-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate as alight yellow solid (2.13 g, 53% yield). Mass spectrum m/z 403 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H), 7.40-7.26 (m, 7H), 6.62 (d,J=8.1 Hz, 1H), 5.08-4.94 (m, 2H), 3.79-3.65 (m, 1H), 3.41 (d, J=10.1 Hz,1H), 3.20 (d, J=11.0 Hz, 1H), 2.60 (t, J=10.7 Hz, 1H), 2.43-2.16 (m,7H), 1.92 (d, J=9.5 Hz, 1H), 1.86-1.78 (m, 1H), 1.71 (d, J=11.2 Hz, 1H),1.40-1.26 (m, 1H).

Intermediate 13

A suspension of (S)-benzyl(1-(7-cyano-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate (1.69 g,3.44 mmol) in 80% aqueous H₂SO₄ (11.3 mL, 172 mmol) was heated at 60° C.After 2.5 h the mixture was cooled to room temperature, then poured ontoice. The pH of the mixture was adjusted to about 9-10 with concentratedaqueous KOH. The resulting mixture was extracted with 3:1chloroform-isopropanol. The organic phase was dried and concentrated toprovide(S)-4-(3-aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide as abrown solid (1.66 g, 50% purity, 99% yield) which was used withoutfurther purification. Mass spectrum m/z 287 (M+H)⁺.

Intermediate 14(R)-4-(3-Aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting (R)-benzyl piperidin-3-ylcarbamate for (S)-benzylpiperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile[Intermediate 11] was converted into(R)-4-(3-aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide. Massspectrum m/z 287 (M+H)⁺.

Intermediate 15(RS)-4-(3-Aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting (RS)-benzyl piperidin-3-ylcarbamate for (S)-benzylpiperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile[Intermediate 11] was converted into(RS)-4-(3-aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide.Mass spectrum m/z 287 (M+H)⁺.

Intermediate 16(S)-4-(3-Aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into(S)-4-(3-aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide.Mass spectrum m/z 305 (M+H)⁺.

Intermediate 172,3-Dimethyl-4-(piperidin-4-ylamino)-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting benzyl 4-aminopiperidine-1-carboxylate for (S)-benzylpiperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile[Intermediate 11] was converted into2,3-dimethyl-4-(piperidin-4-ylamino)-1H-indole-7-carboxamide. Massspectrum m/z 287 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 7.40(d, J=8.1 Hz, 1H), 7.21-6.95 (m, 2H), 6.08 (d, J=8.4 Hz, 1H), 4.87 (d,J=7.9 Hz, 1H), 3.89-3.76 (m, 1H), 3.46 (br. s., 1H), 3.00-2.85 (m, 2H),2.67-2.54 (m, 2H), 2.37 (s, 3H), 2.26 (s, 3H), 1.94 (d, J=9.5 Hz, 2H),1.36 (d, J=9.0 Hz, 2H).

Intermediate 185-Fluoro-2,3-dimethyl-4-(piperidin-4-ylamino)-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting benzyl 4-aminopiperidine-1-carboxylate for (S)-benzylpiperidin-3-ylcarbamate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into5-fluoro-2,3-dimethyl-4-(piperidin-4-ylamino)-1H-indole-7-carboxamide.Mass spectrum m/z 305 (M+H)⁺.

Intermediate 19(RS)-2,3-Dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting (RS)-benzyl 3-aminopyrrolidine-1-carboxylate for (S)-benzylpiperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile[Intermediate 11] was converted into(RS)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide. Massspectrum m/z 273 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.41 (s, 1H),7.77-7.49 (m, 1H), 7.42 (d, J=7.9 Hz, 1H), 6.85 (br. s., 1H), 6.05 (d,J=8.5 Hz, 1H), 5.12 (d, J=6.1 Hz, 1H), 4.00 (br. s., 1H), 3.11 (dd,J=11.0, 6.1 Hz, 1H), 3.02-2.96 (m, 1H), 2.86-2.81 (m, 1H), 2.78 (dd,J=11.9, 3.4 Hz, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 2.17-2.09 (m, 1H), 1.67(d, J=5.5 Hz, 1H).

Intermediate 20(RS)-5-Fluoro-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting (RS)-benzyl 3-aminopyrrolidine-1-carboxylate for (S)-benzylpiperidin-3-ylcarbamate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into(RS)-5-fluoro-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide.Mass spectrum m/z 291 (M+H)⁺.

Intermediate 21(S)-5-Fluoro-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide

Intermediate 21A: (S)-Benzyl3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidine-1-carboxylate

Following the procedure use to prepare Intermediate 13A but substituting(S)-benzyl 3-aminopyrrolidine-1-carboxylate for (S)-benzylpiperidin-3-ylcarbamate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into (S)-benzyl3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidine-1-carboxylatein 39% yield. Mass spectrum m/z 407 (M+H)⁺.

Intermediate 21

Following the procedure used to prepare Intermediate 13 fromIntermediate 13A, (S)-benzyl3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidine-1-carboxylatewas converted into(S)-5-fluoro-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamidein 77% yield. Mass spectrum m/z 291 (M+H)⁺.

Intermediate 22(RS)-4-(3-Aminopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting (RS)-benzyl pyrrolidin-3-ylcarbamate for (S)-benzylpiperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile[Intermediate 11] was converted into(RS)-4-(3-aminopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide.Mass spectrum m/z 273 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H),7.73 (dd, J=8.7, 5.6 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 6.96 (br. s., 3H),6.44 (d, J=8.1 Hz, 1H), 3.56-3.46 (m, 1H), 3.26-3.08 (m, 3H), 2.82 (dd,J=9.5, 5.3 Hz, 1H), 2.33 (s, 3H), 2.30 (s, 3H), 2.19-2.11 (m, 1H),1.61-1.50 (m, 1H).

Intermediate 23(R)-4-(3-Aminopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting (R)-benzyl pyrrolidin-3-ylcarbamate for (S)-benzylpiperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile[Intermediate 11] was converted into(R)-4-(3-aminopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide.Mass spectrum m/z 273 (M+H)⁺.

Intermediate 24(S)-4-(3-Aminopyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting (S)-benzyl pyrrolidin-3-ylcarbamate for (S)-benzylpiperidin-3-ylcarbamate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into(S)-4-(3-aminopyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide.Mass spectrum m/z 291 (M+H)⁺.

Intermediate 25(RS)-2,3-Dimethyl-4-(piperidin-3-ylamino)-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting (RS)-benzyl 3-aminopiperidine-1-carboxylate for (S)-benzylpiperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile[Intermediate 11] was converted into(RS)-2,3-dimethyl-4-(piperidin-3-ylamino)-1H-indole-7-carboxamide. Massspectrum m/z 287 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.40 (s, 1H), 7.94(s, 1H), 7.56 (br. s., 1H), 7.41 (d, J=7.9 Hz, 1H), 6.81 (br. s., 1H),6.08 (d, J=8.5 Hz, 1H), 5.40-5.23 (m, 1H), 3.77-3.56 (m, 2H), 3.06 (d,J=12.2 Hz, 1H), 2.78 (br. s., 1H), 2.70-2.61 (m, 2H), 2.38 (s, 3H), 2.26(s, 3H), 1.86-1.78 (m, 1H), 1.69-1.60 (m, 2H), 1.52-1.41 (m, 1H).

Intermediate 26(S)-2,3-Dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide

Intermediate 26A: (S)-tert-Butyl3-((7-cyano-2,3-dimethyl-1H-indol-4-yl)amino) pyrrolidine-1-carboxylate

A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate11](0.400 g, 1.61 mmol), (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate(0.336 g, 1.80 mmol) and 1,4-dioxane (15 mL) was bubbled with nitrogenfor 5 min 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.050 g, 0.080mmol), tris(dibenzylideneacetone)dipalladium (0.074 g, 0.080 mmol) andCs₂CO₃ (0.732 g, 2.25 mmol) were added, and the mixture was sealed undera nitrogen atmosphere and heated at 100° C. After 19 h, the mixture wascooled to room temperature. Water (50 mL) and EtOAc (50 mL) were added,and the mixture was extracted with EtOAc (3×50 mL). The combined organicextracts were washed with brine, dried and concentrated. The residue wassubjected to column chromatography on silica gel, eluting withEtOAc-hexanes, to provide (S)-tert-butyl3-((7-cyano-2,3-dimethyl-1H-indol-4-yl)amino) pyrrolidine-1-carboxylateas a pale yellow solid (0.47 g, 79% yield). Mass spectrum m/z 355(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.16 (s, 1H), 7.24 (d, J=8.1 Hz,1H), 6.23 (d, J=8.4 Hz, 1H), 5.36 (br. s., 1H), 4.25-4.08 (m, 1H),3.69-3.57 (m, 1H), 3.48-3.37 (m, 1H), 3.38-3.31 (m, 1H), 3.27-3.16 (m,1H), 2.34 (s, 3H), 2.24 (s, 3H), 2.22-2.13 (m, 1H), 1.97-1.86 (m, 1H),1.49-1.31 (m, 9H).

Intermediate 26B:(S)-2,3-Dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carbonitrile TFASalt

A mixture of (S)-tert-butyl3-((7-cyano-2,3-dimethyl-1H-indol-4-yl)amino) pyrrolidine-1-carboxylate(0.470 g, 1.33 mmol) and DCM (5 mL) was cooled to 0° C., treated withTFA (5 mL) and stirred for 1 h. The mixture was concentrated to providecrude (S)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carbonitrileTFA salt, used without further purification. Mass spectrum m/z 255(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.23 (s, 1H), 8.93-8.72 (m, 1H),7.27 (d, J=8.1 Hz, 1H), 6.21 (d, J=8.6 Hz, 1H), 5.48 (br. s., 1H), 4.27(br. s., 1H), 3.54-3.44 (m, 1H), 3.42-3.33 (m, 1H), 3.31-3.17 (m, 2H),2.38 (s, 3H), 2.36-2.28 (m, 1H), 2.26 (s, 3H), 2.09-2.00 (m, 1H).

Intermediate 26

A mixture of(S)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carbonitrile TFAsalt (488 mg, 1.33 mmol) and 80% aqueous H₂SO₄ (3 mL) was heated at 60°C. After 2 h, the mixture was cooled to room temperature, then wasslowly added to 10 M aqueous NaOH at 0° C. The aqueous supernatant wasremoved from the resulting sticky brown solid by decantation. Water wasadded to the solid and the mixture was extracted with EtOAc (4×50 mL).The combined organic extracts were washed with brine, dried andconcentrated to provide(S)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide as anorange solid (270 mg, 75% yield). Mass spectrum m/z 273 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 7.59 (br. s., 1H), 7.42 (d, J=8.4Hz, 1H), 6.85 (br. s., 1H), 6.05 (d, J=8.4 Hz, 1H), 5.07 (d, J=6.8 Hz,1H), 3.99-3.89 (m, 1H), 3.30 (br. s., 1H), 3.04 (dd, J=11.1, 6.1 Hz,1H), 2.98-2.88 (m, 1H), 2.82-2.67 (m, 2H), 2.36 (s, 3H), 2.26 (s, 3H),2.10 (td, J=13.4, 7.5 Hz, 1H), 1.68-1.53 (m, 1H).

Intermediate 27(R)-2,3-Dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide

Following the procedures used to prepared Intermediate 26 butsubstituting (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate for(S)-tert-butyl 3-aminopyrrolidine-1-carboxylate,4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 11] wasconverted into(R)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide. Massspectrum and ¹H NMR were the same as those for Intermediate 26.

Intermediate 28(S)-2,3-Dimethyl-4-(methyl(pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 26 butsubstituting (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate for(S)-tert-butyl 3-aminopyrrolidine-1-carboxylate,4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 11] wasconverted into(S)-2,3-dimethyl-4-(methyl(pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide.Mass spectrum m/z 287 (M+H)⁺.

Intermediate 29(RS-cis)-5-Fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide

Intermediate 29A: Ethyl4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate

A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid[Intermediate 2C] (2.00 g, 6.99 mmol) and concentrated H₂SO₄ (0.373 mL,6.99 mmol) in ethanol (30 mL) was stirred at reflux for 6 days. Themixture was cooled to room temperature and concentrated. The residue waspartitioned between EtOAc and water, and the organic layer was dried andconcentrated. The residue was purified by column chromatography onsilica gel, eluting with EtOAc-hexanes (gradient from 0-100%) to provideethyl 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate as anoff-white solid (1.67 g, 72% yield). Mass spectrum m/z 314, 316 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 9.57 (br. s., 1H), 7.54 (d, J=9.4 Hz, 1H),4.45 (q, J=7.2 Hz, 2H), 2.49 (d, J=0.5 Hz, 3H), 2.40 (s, 3H), 1.46 (t,J=7.2 Hz, 3H).

Intermediate 29B: (RS-cis)-tert-Butyl6-(7-(ethoxycarbonyl)-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate

Following the procedure used to prepare Intermediate 13A butsubstituting (RS-cis)-tert-butyloctahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate for (S)-benzylpiperidine-3-ylcarbamate, ethyl4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate was converted into(RS-cis)-tert-butyl6-(7-(ethoxycarbonyl)-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylateas a light yellow glassy solid in 61% yield. Mass spectrum m/z 460(M+H)⁺.

Intermediate 29C:(RS-cis)-4-(1-(tert-Butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylicacid

A mixture of (RS-cis)-tert-butyl6-(7-(ethoxycarbonyl)-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate(91 mg, 0.198 mmol) and 1 M aqueous NaOH (1.98 mL, 1.98 mmol) in THF (1mL) and MeOH (1 mL) was stirred at room temperature overnight. Themixture was treated with 1 M aqueous HCl (to pH about 6) and extractedtwice with EtOAc. The combined organic phases were dried andconcentrated to provide(RS-cis)-4-(1-(tert-butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylicacid as a yellow glassy solid (73 mg, 85% yield), used without furtherpurification. Mass spectrum m/z 432 (M+H)⁺.

Intermediate 29D: (RS-cis)-tert-Butyl6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate

A solution of(RS-cis)-4-(1-(tert-butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylicacid (73 mg, 0.169 mmol), NH₄Cl (45.2 mg, 0.846 mmol) and HATU (70.8 mg,0.186 mmol) in DMF (1 mL) was treated with triethylamine (0.118 mL,0.846 mmol) and stirred at room temperature for 2 h. The mixture wasdiluted with DCM, washed with water, dried and concentrated. The residuewas purified by column chromatography on silica gel, eluting withEtOAc-hexanes (gradient from 0-100%), to provide (RS-cis)-tert-butyl6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylateas a yellow gum (74.2 mg, 92% yield). Mass spectrum m/z 431 (M+H)⁺.

Intermediate 29

A solution of (RS-cis)-tert-butyl6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate(70 mg, 0.163 mmol) and TFA (0.5 mL, 6.49 mmol) in DCM (1.5 mL) wasstirred at room temperature for 30 min. The mixture was concentrated,and the residue was partitioned between DCM and saturated aqueousNaHCO₃. The organic phase was dried and concentrated to provide(RS-cis)-5-fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamideas a yellow glassy solid (53 mg, 99% yield), used without furtherpurification. Mass spectrum m/z 331 (M+H)⁺.

Alternative Synthesis of Intermediate 29

Following the procedures used to prepare Intermediate 26 butsubstituting (RS-cis)-tert-butyloctahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate for (S)-tert-butyl3-aminopyrrolidine-1-carboxylate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into(RS-cis)-5-fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide.

Intermediate 30(RS-cis)-5-Fluoro-4-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 26 butsubstituting (RS-cis)-tert-butylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate for (S)-tert-butyl3-aminopyrrolidine-1-carboxylate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into(RS-cis)-5-fluoro-4-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide.Mass spectrum m/z 317 (M+H)⁺.

Intermediate 31(RS-cis)-5-Fluoro-4-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 26 butsubstituting (RS-cis)-tert-butylhexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate for (S)-tert-butyl3-aminopyrrolidine-1-carboxylate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into(RS-cis)-5-fluoro-4-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide.Mass spectrum m/z 317 (M+H)⁺.

Intermediate 32cis-5-Fluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 26 butsubstituting cis-tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate for (S)-tert-butyl3-aminopyrrolidine-1-carboxylate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted intocis-5-fluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide.Mass spectrum m/z 317 (M+H)⁺.

Intermediate 33(S)-4-(3-(Ethylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 26 butsubstituting (S)-tert-butyl ethyl(piperidin-3-yl)carbamate for(S)-tert-butyl 3-aminopyrrolidine-1-carboxylate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into(S)-4-(3-(ethylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide.

Intermediate 34 2,3-Dimethyl-4-(piperazin-1-yl)-1H-indole-7-carboxamide

Intermediate 34A:2,3-Dimethyl-4-(piperazin-1-yl)-1H-indole-7-carbonitrile

A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate11](100 mg, 0.401 mmol), piperazine (69.2 mg, 0.803 mmol),tris(dibenzylideneacetone) dipalladium (18.4 mg, 0.020 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (12.5 mg, 0.020 mmol) andCs₂CO₃ (183 mg, 0.562 mmol) in 1,4-dioxane (4 mL) in a sealed reactionvessel was subjected to three evacuate-fill cycles with nitrogen. Themixture was heated at 100° C. for 16 h, then was cooled to roomtemperature, filtered and the collected precipitate was washed withEtOAc. The filtrate was concentrated and the residue was subjected tocolumn chromatography on silica gel (12 g), eluting with MeOH-DCM(gradient from 0-30%), to provide2,3-dimethyl-4-(piperazin-1-yl)-1H-indole-7-carbonitrile as a lightbrown solid (56 mg, 55% yield). Mass spectrum m/z 255 (M+H)⁺.

Intermediate 34

A mixture of 2,3-dimethyl-4-(piperazin-1-yl)-1H-indole-7-carbonitrile(56 mg, 0.220 mmol) and 80% aqueous H₂SO₄ (2 mL) was heated at 60° C.for 3 h. The mixture was poured onto ice and the pH of the resultingmixture was adjusted to about 10 with solid KOH. The mixture was thenextracted three times with a mixture of 3:1 DCM-isopropanol. Thecombined organic phases were washed with water, dried and concentratedto provide 2,3-dimethyl-4-(piperazin-1-yl)-1H-indole-7-carboxamide as ayellow solid (35 mg, 58% yield). Mass spectrum m/z 273 (M+H)⁺.

Intermediate 35(RS)-2,3-Dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide

Intermediate 35A: (RS)-tert-Butyl3-(((benzyloxy)carbonyl)(methyl)amino)piperidine-1-carboxylate

A solution of (RS)-tert-butyl 3-(methylamino)piperidine-1-carboxylate(1.60 g, 7.47 mmol) and DIEA (1.57 mL, 8.96 mmol) in DCM (29.9 mL) wascooled to 0° C. and slowly treated with benzyl chloroformate (1.08 mL,7.54 mmol). The resulting mixture was stirred at room temperature for 1h, then was concentrated. The residue was subjected to columnchromatography on silica gel to provide (RS)-tert-butyl3-(((benzyloxy)carbonyl)(methyl)amino)piperidine-1-carboxylate as acolorless oil (2.56 g, 98% yield). Mass spectrum m/z 371 (M+Na)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.40-7.29 (m, 5H), 5.16 (s, 2H), 4.21-3.81 (m, 3H),2.87 (s, 3H), 2.76 (t, J=10.9 Hz, 1H), 2.56 (t, J=11.9 Hz, 1H), 1.85 (d,J=12.3 Hz, 1H), 1.78-1.70 (m, 1H), 1.66-1.60 (m, 1H), 1.45 (br. s.,10H).

Intermediate 35B: (RS)-Benzylmethyl(piperidin-3-yl)carbamate

A solution of (RS)-tert-butyl3-(((benzyloxy)carbonyl)(methyl)amino)piperidine-1-carboxylate (2.56 g,7.34 mmol) in DCM (14.7 mL) was cooled to 0° C. and treated slowly withTFA (2.80 mL, 36.7 mmol). The resulting mixture was stirred at roomtemperature for 16 h, then was concentrated. The residue was partitionedbetween 1 M aqueous NaOH and EtOAc. The organic phase was washed withbrine, dried and concentrated to provide (RS)-benzylmethyl(piperidin-3-yl)carbamate as a light yellow oil (1.71 g, 94%yield). Mass spectrum m/z 249 (M+H)⁺.

Intermediate 35

Following the procedures used to prepare Intermediate 13 butsubstituting (RS)-benzyl methyl(piperidin-3-yl)carbamate for (S)-benzylpiperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile[Intermediate 11] was converted into(RS)-2,3-dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide.Mass spectrum m/z 301 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.60 (s, 1H),7.81 (br. s., 1H), 7.47 (d, J=8.1 Hz, 1H), 7.10 (br. s., 1H), 6.53 (d,J=8.4 Hz, 1H), 2.70 (br. s., 1H), 2.59 (br. s., 1H), 2.37-2.29 (m, 10H),1.97 (d, J=10.4 Hz, 1H), 1.89 (s, 3H), 1.81-1.65 (m, 2H), 1.13 (br. s.,1H).

Intermediate 36(S)-5-Fluoro-2,3-dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 13 butsubstituting (S)-tert-butyl methyl(piperidin-3-yl)carbamate for(S)-benzyl piperidin-3-ylcarbamate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into(S)-5-fluoro-2,3-dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide.Mass spectrum m/z 319 (M+H)⁺.

Intermediate 37(S)-5-Fluoro-2,3-dimethyl-4-(methyl(pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide

Intermediate 37A: (S)-Benzyl3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)(methyl)amino)-pyrrolidine-1-carboxylate

A mixture of (S)-benzyl3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidine-1-carboxylate [Intermediate 21A] (0.114 g, 0.280 mmol),paraformaldehyde (0.025 g, 0.841 mmol), acetic acid (0.048 mL, 0.841mmol), and sodium cyanoborohydride (0.035 g, 0.561 mmol) in MeOH (2.5mL) was stirred at room temperature overnight. The mixture was thenheated at 50° C. for about 24 h, then was stirred at room temperatureovernight. The mixture was diluted with EtOAc and washed sequentiallywith water and brine. The organic layer was collected, and the aqueouslayers were sequentially extracted twice with EtOAc. The combinedorganic layers were dried and concentrated. The residue was subjected tocolumn chromatography on silica gel, eluting with EtOAc-hexane (5%, 13%and 20%, sequentially), to give (S)-benzyl3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)(methyl)amino)pyrrolidine-1-carboxylateas a colorless viscous oil (0.049 g, 42% yield). Mass spectrum m/z 421(M+H)⁺.

Intermediate 37

Following the procedure used in the last step of the preparation ofIntermediate 13, (S)-benzyl3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)(methyl)amino)pyrrolidine-1-carboxylate was converted into(S)-5-fluoro-2,3-dimethyl-4-(methyl(pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide in 94% yield. Massspectrum m/z 305 (M+H)⁺.

Intermediate 38(RS)-2,3-Dimethyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide, TFA Salt

Intermediate 38A: tert-Butyl3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate1](175 mg, 0.655 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(203 mg, 0.655 mmol), 1,4-dioxane (5 mL) and water (1 mL) was bubbledwith nitrogen for 5 min and treated with PdCl₂(dppf) DCM adduct (32.1mg, 0.039 mmol) and Cs₂CO₃ (640 mg, 1.97 mmol). The mixture was sealedunder an atmosphere of nitrogen and heated at 90° C. After 15 h themixture was cooled to room temperature and diluted with EtOAc (15 mL)and water (15 mL). The layers were separated and the aqueous layer wasextracted three times with EtOAc. The combined organic extracts weredried and concentrated. The residue was subjected to columnchromatography on silica gel, eluting with EtOAc-hexanes, to providetert-butyl3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylateas a yellow solid (174 mg, 69% yield). Mass spectrum m/z 370 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 10.69 (s, 1H), 7.91 (br. s., 1H), 7.50 (d,J=7.7 Hz, 1H), 7.23 (br. s., 1H), 6.75 (d, J=7.5 Hz, 1H), 6.62 (br. s.,1H), 3.62-3.56 (m, 2H), 2.40-2.29 (m, 5H), 2.13 (s, 3H), 1.97-1.87 (m,2H), 1.55-1.31 (m, 9H).

Intermediate 38B: tert-Butyl(RS)-3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)piperidine-1-carboxylate

A mixture of tert-butyl3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(94 mg, 0.254 mmol), DMF (1 mL) and MeOH (5 mL) was treated withpalladium on carbon (94 mg) and stirred at room temperature under anatmosphere of hydrogen. After 20 h, additional palladium on carbon (94mg) was added and stirring under an atmosphere of hydrogen was continuedfor a total of three days. The mixture was filtered and the filtrate wasconcentrated. The residue was dissolved in EtOAc, washed with water, andthe aqueous layer was extracted three times with EtOAc. The organicextracts were combined, washed sequentially with brine and 10% aqueousLiCl, dried and concentrated to provide (RS)-tert-butyl3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)piperidine-1-carboxylate as ayellow solid (72.5 mg, 73% yield). Mass spectrum m/z 372 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 10.66 (s, 1H), 7.91 (br. s., 1H), 7.51 (d, J=7.9Hz, 1H), 7.22 (br. s., 1H), 6.87 (d, J=7.9 Hz, 1H), 4.15-4.06 (m, 1H),3.50-3.38 (m, 1H), 2.93-2.73 (m, 2H), 2.60 (s, 6H), 1.96-1.88 (m, 1H),1.86-1.67 (m, 2H), 1.61-1.47 (m, 1H), 1.40 (s, 9H), 1.28-1.21 (m, 1H).

Intermediate 38

A solution of (RS)-tert-butyl 3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)piperidine-1-carboxylate (74 mg, 0.179 mmol) in DCM (2 mL) was cooled to0° C. and treated slowly with TFA (2 mL). The mixture was stirred atroom temperature for 2 h, then was concentrated to provide(RS)-2,3-dimethyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide TFA salt asa yellow solid (76 mg, quantitative yield). Mass spectrum m/z 272(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 7.93 (br. s., 1H),7.54 (d, J=7.9 Hz, 1H), 7.27 (br. s., 1H), 6.89 (d, J=7.9 Hz, 1H),3.86-3.75 (m, 1H), 3.35 (d, J=11.9 Hz, 2H), 3.27-3.13 (m, 1H), 3.03-2.84(m, 1H), 2.41-2.32 (m, 6H), 1.93 (d, J=11.9 Hz, 1H), 1.88-1.70 (m, 2H),1.30-1.22 (m, 1H), 0.95 (d, J=7.0 Hz, 1H).

Intermediate 39 (RS)-3-Methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide

Intermediate 39A: tert-Butyl3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Following the procedure used to prepare Intermediate 38A,4-bromo-3-dimethyl-1H-indole-7-carboxamide [Intermediate 4] wasconverted into tert-butyl3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylatein 53% yield. Mass spectrum m/z 356 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ7.42-7.27 (m, 1H), 7.16-7.03 (m, 1H), 6.97-6.73 (m, 2H), 3.75-3.59 (m,2H), 2.43 (br. s., 2H), 2.30 (s, 3H), 2.02 (br. s., 2H), 1.54-1.37 (m,9H).

Intermediate 39B:3-Methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide

Following the procedure used to prepare Intermediate 38 fromIntermediate 38B, followed by neutralization of the resulting TFA salt,tert-butyl3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylatewas converted into3-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide in93% yield. Mass spectrum m/z 256 (M+H)⁺.

Intermediate 39

A solution of3-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide (20mg, 0.078 mmol) in MeOH (3 mL) was treated with palladium on charcoal(8.3 mg) and stirred under a hydrogen atmosphere for 12 h at roomtemperature. The mixture was filtered through CELITE® and the filtratewas concentrated to provide(RS)-3-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide as a whitesolid (20 mg, 99% yield). Mass spectrum m/z 258 (M+H)⁺.

Intermediate 40(RS)-2,3-Dimethyl-4-(pyrrolidin-3-yl)-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 38 butsubstituting tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylatefor tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate,4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 1] wasconverted into(RS)-2,3-dimethyl-4-(pyrrolidin-3-yl)-1H-indole-7-carboxamide. Massspectrum m/z 258 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 8.92(br. s., 1H), 7.96 (s, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.29 (br. s., 1H),6.99 (d, J=7.9 Hz, 1H), 4.35-4.17 (m, 1H), 3.69-3.57 (m, 1H), 3.48-3.39(m, 1H), 3.38-3.30 (m, 1H), 3.27-3.17 (m, 1H), 2.37 (s, 6H), 2.36-2.29(m, 1H), 2.15-2.03 (m, 1H).

Intermediate 414-(3-Amino-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide

A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate1](0.25 g, 0.936 mmol),2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to the procedure of U.S. Pat. No. 8,084,620,Intermediate 50-1](0.229 g, 0.983 mmol), andtetrakis(triphenylphosphine)palladium (0.054 g, 0.047 mmol) in toluene(10.8 mL) and ethanol (3.6 mL) was bubbled with argon for about 2 to 3min. The mixture was treated with 2 M aqueous Na₂CO₃ (1.17 mL, 2.34mmol), bubbled again with argon, and the reaction vessel was sealedunder argon and heated at 90° C. After 16 h the mixture was cooled toroom temperature and partitioned between water and EtOAc. The organicphase was concentrated and the residue was subjected to columnchromatography on silica gel (24 g), eluting with EtOAc-hexanes(gradient from 50-70%), to provide4-(3-amino-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide as alight yellow solid (0.142 g, 52% yield). Mass spectrum m/z 294 (M+H)⁺.

Intermediate 42(RS)-5-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide

Intermediate 42A: tert-Butyl(RS)-5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Intermediate 2] (0.200 g, 0.701 mmol), tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.302 g, 0.842 mmol), 2 M aqueous K₃PO₄ (1.05 mL, 2.10 mmol) and THF (4mL) was subjected to 3 evacuate-fill cycles with nitrogen. PdCl₂(dppf)DCM adduct (0.023 g, 0.035 mmol) was added, and the mixture wassubjected to 2 more evacuate-fill cycles with nitrogen. The mixture wasstirred at room temperature overnight, then was diluted with EtOAc,washed sequentially with water and brine, dried and concentrated. Theresidue was subjected to column chromatography on silica gel, elutingwith EtOAc-hexanes, to provide tert-butyl(RS)-5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylateas an off-white solid (0.307 g, quantitative yield). Mass spectrum m/z438 (M+H)⁺.

Intermediate 42

A mixture of tert-butyl(RS)-5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.312 g, 0.713 mmol) and TFA (5 mL) was stirred at room temperature for30 min. The mixture was concentrated under reduced pressure, and theresidue was diluted with EtOAc, washed sequentially with 1.5 M aqueousNa₂HPO₄ and brine, dried and concentrated to provide(RS)-5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideas an orange solid (0.241 g, quantitative yield). Mass spectrum m/z 338(M+H)⁺.

Intermediate 435-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroquinolin-6-yl)-1H-indole-7-carboxamideTFA salt

Intermediate 43A: tert-Butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

Following the procedure used to prepare Intermediate 9, tert-butyl6-bromo-3,4-dihydroquinoline-1(2H)-carboxylate was converted intotert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylateas a white solid in 82% yield. Mass spectrum m/z 360 (M+H)⁺, 304(M+H—C₄Hs)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.71-7.66 (m, 1H), 7.62-7.57 (m,1H), 7.56 (s, 1H), 3.77-3.68 (m, 2H), 2.79 (t, J=6.6 Hz, 2H), 1.93 (dt,J=12.5, 6.4 Hz, 2H), 1.54 (s, 9H), 1.36 (s, 12H).

Intermediate 43

Following the procedures used to prepare Intermediate 42 but omittingthe treatment with aqueous Na₂HPO₄ in the last step, tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylatewas converted into5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroquinolin-6-yl)-1H-indole-7-carboxamideTFA salt. Mass spectrum m/z 338 (M+H)⁺.

Intermediate 445-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 43, tert-butyl7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate was converted into5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-indole-7-carboxamide,TFA salt. Mass spectrum m/z 338 (M+H)⁺.

Intermediate 455-Fluoro-4-(isoindolin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide TFASalt

Following the procedures used to prepare Intermediate 43, tert-butyl4-bromoisoindoline-2-carboxylate was converted into5-fluoro-4-(isoindolin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide, TFAsalt. Mass spectrum m/z 324 (M+H)⁺.

Intermediate 465-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 43, tert-butyl7-bromo-3,4-dihydroquinoline-1(2H)-carboxylate was converted into5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-indole-7-carboxamide,TFA salt. Mass spectrum m/z 338 (M+H)⁺.

Intermediate 475-Fluoro-4-(isoindolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide TFASalt

Following the procedures used to prepare Intermediate 43, tert-butyl5-bromo-isoindoline-2-carboxylate was converted into5-fluoro-4-(isoindolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide, TFAsalt. Mass spectrum m/z 324 (M+H)⁺.

Intermediate 48(RS-cis)-5-Fluoro-2,3-dimethyl-4-(1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-1H-indole-7-carboxamideTFA Salt

Intermediate 48A: (RS-cis)-tert-Butyl7-bromo-1a,2-dihydro-1H-cyclopropa[c]quinoline-3(7bH)-carboxylate

A solution of(RS-cis)-7-bromo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinoline[prepared according to procedures described in Example 9 of PCTPublication No. WO 2012/149236] (700 mg, 3.12 mmol) and di-tert-butyldicarbonate (1.08 mL, 4.69 mmol) in 1,4-dioxane (5.0 mL) was stirred at80° C. for 18. The cooled mixture was diluted with saturated aqueousNaHCO₃(15 mL) and extracted with EtOAc (20 mL). The organic layer wasdried and concentrated, and the residue was subjected to columnchromatography on silica gel, eluting with EtOAc-hexanes (gradient from0-50%), to provide (RS-cis)-tert-butyl7-bromo-1a,2-dihydro-1H-cyclopropa[c]quinoline-3(7bH)-carboxylate as alight brown gum (963 mg, 67% yield). Mass spectrum m/z 324, 326(M+H−C₄H₈)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.33 (dd, J=8.0, 1.2 Hz, 1H),7.25 (d, J=7.9 Hz, 1H), 6.95 (t, J=8.0 Hz, 1H), 4.51 (dd, J=13.0, 1.3Hz, 1H), 2.94 (d, J=12.1 Hz, 1H), 2.44 (td, J=8.6, 4.5 Hz, 1H), 1.88(dtq, J=8.0, 5.8, 1.9 Hz, 1H), 1.47 (s, 9H), 1.11 (td, J=8.3, 5.3 Hz,1H), 0.74 (q, J=4.9 Hz, 1H).

Intermediate 48

Following the procedures used to prepare Intermediate 43,(RS-cis)-tert-butyl7-bromo-1a,2-dihydro-1H-cyclopropa[c]quinoline-3(7bH)-carboxylate wasconverted into(RS-cis)-5-fluoro-2,3-dimethyl-4-(1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-1H-indole-7-carboxamide,TFA salt. Mass spectrum m/z 350 (M+H)⁺.

Intermediate 494-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 48,8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine [prepared according toprocedures described in Example 10 of PCT Publication No. WO2012/149236] was converted into4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,TFA salt. Mass spectrum m/z 340 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ10.66 (s, 1H), 8.01 (br. s., 1H), 7.45 (d, J=10.8 Hz, 1H), 7.40 (br. s.,1H), 6.77-6.68 (m, 1H), 6.63 (dd, J=7.9, 1.7 Hz, 1H), 6.37 (dd, J=7.5,1.6 Hz, 1H), 4.08-3.92 (m, 2H), 3.31-3.22 (m, 2H), 2.29 (s, 3H), 1.62(s, 3H).

Intermediate 50(RS)-5-Fluoro-4-(4-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamideTFA Salt

Intermediate 50A: tert-Butyl5-bromo-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of 5-bromo-2,3-dihydroisoquinolin-4(1H)-one hydrochloride(1.05 g, 4.00 mmol), di-tert-butyl dicarboxylate (1.02 mL, 4.40 mmol)and triethylamine (1.67 mL, 12.0 mmol) in MeOH (20 mL) was stirred atroom temperature for 90 min. The mixture was concentrated and theresidue was subjected to column chromatography on silica gel, elutingwith EtOAc-hexanes (gradient from 0-30%), to provide tert-butyl5-bromo-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate as a gum (640mg, 47% yield). Mass spectrum m/z 270, 272 (M+H−C₄Hs)⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.67 (dt, J=7.9, 0.6 Hz, 1H), 7.40-7.32 (m, 1H), 7.31-7.26 (m,1H), 4.75 (s, 2H), 4.37 (s, 2H), 1.50 (s, 9H).

Intermediate 50B: (RS)-tert-Butyl5-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

A solution of tert-butyl5-bromo-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 0.460mmol) in THF (3.0 mL) and MeOH (3.0 mL) was treated with sodiumborohydride (17.4 mg, 0.460 mmol). The mixture was stirred at roomtemperature for 60 min and concentrated. The residue was subjected tocolumn chromatography on silica gel, eluting with EtOAc-hexanes(gradient from 0-100%) to provide (RS)-tert-butyl5-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate as a whiteglassy solid (137 mg, 86% yield). Mass spectrum m/z 254, 256(M+H—(H₂O+C₄H))⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.50 (dd, J=8.3, 0.6 Hz,1H), 7.21-7.15 (m, 1H), 7.14-7.09 (m, 1H), 5.02 (br. s., 2H), 4.48 (d,J=10.8 Hz, 1H), 4.26 (d, J=17.2 Hz, 1H), 3.19 (d, J=12.3 Hz, 1H), 2.36(br. s., 1H), 1.52 (s, 9H).

Intermediate 50C: (RS)-tert-Butyl5-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

A solution of (RS)-tert-butyl5-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (137 mg,0.417 mmol) in DCM (5.0 mL) at −78° C. was treated dropwise withdiethylaminosulfur trifluoride [DAST] (0.331 mL, 2.51 mmol) and themixture was stirred at −78° C. for 10 min. The mixture was treated withsaturated aqueous NaHCO₃ (5.0 mL). The DCM layer was separated, driedand concentrated. The residue was subjected to column chromatography onsilica gel, eluting with EtOAc-hexanes (gradient from 0-100%), toprovide (RS)-tert-butyl5-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate as acolorless gum (100 mg, 69% yield). Mass spectrum m/z 254, 256(M+H−(HF+C₄Hs))⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J=7.9 Hz, 1H), 7.25(td, J=7.8, 2.1 Hz, 1H), 7.20-7.13 (m, 1H), 5.95-5.64 (m, 1H), 5.25-4.91(m, 1H), 4.69 (br. s., 1H), 4.26 (br. s., 1H), 3.43-3.03 (m, 1H), 1.52(s, 9H).

Intermediate 50

Following the procedures used to prepare Intermediate 43,(RS)-tert-butyl5-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate wasconverted into(RS)-5-fluoro-4-(4-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide,TFA salt. Mass spectrum m/z 356 (M+H)⁺.

Intermediate 51 N-(3-Bromobenzyl)acrylamide

A solution of (3-bromophenyl)methanamine (0.500 g, 2.69 mmol) in DCM(13.4 mL) at 0° C. was treated with DIEA (0.939 mL, 5.37 mmol), then wastreated dropwise with acryloyl chloride (0.240 mL, 2.96 mmol). Themixture was stirred at room temperature for 3 h, then was concentrated.The residue was subjected to column chromatography on silica gel (24 g),eluting with EtOAc-hexanes (gradient from 30-45%), to provideN-(3-bromobenzyl)acrylamide as a white solid (0.476 g, 74% yield). Massspectrum m/z 240, 242 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.40 (m,2H), 7.25-7.19 (m, 2H), 6.35 (dd, J=16.9, 1.3 Hz, 1H), 6.17-6.09 (m,1H), 5.84 (br. s., 1H), 5.71 (dd, J=10.2, 1.4 Hz, 1H), 4.52 (d, J=5.9Hz, 2H).

Intermediate 52 1-(6-Bromoindolin-1-yl)prop-2-en-1-one

Following the procedure used to prepare Intermediate 51, 6-bromoindoline[prepared according to the procedure of PCT Publication No. WO2010/093949, Example 82, Step 1] was converted into1-(6-bromoindolin-1-yl)prop-2-en-1-one in 94% yield. Mass spectrum m/z252, 254 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (br. s., 1H),7.21-7.19 (m, 2H), 6.79-6.66 (m, 1H), 6.31 (dd, J=16.7, 2.2 Hz, 1H),5.84 (dd, J=10.3, 2.2 Hz, 1H), 4.23 (t, J=8.6 Hz, 2H), 3.12 (t, J=8.5Hz, 2H).

Intermediate 53 N-(4-Bromopyridin-2-yl)acrylamide

Following the procedure used to prepare Intermediate 51,4-bromo-2-aminopyridine was converted intoN-(4-bromopyridin-2-yl)acrylamide in 50% yield after purification bypreparative reverse-phase HPLC. Mass spectrum m/z 227, 229 (M+H)⁺.

Intermediate 54 6-Bromo-1-(vinylsulfonyl)indoline

A solution of 6-bromoindoline [prepared according to the procedure ofPCT Publication No. WO 2010/093949, Example 82, Step 1] (0.290 g, 0.732mmol) in DCM (3.7 mL) was cooled to 0° C. and treated with DIEA (0.205mL, 1.17 mmol), then was treated dropwise with 2-chloroethanesulfonylchloride (0.092 mL, 0.879 mmol). The mixture was stirred at roomtemperature for 18 h. The mixture was concentrated and the residue wassubjected to chromatography on silica gel (12 g), eluting withEtOAc-hexanes (gradient from 5-20%), to provide6-bromo-1-(vinylsulfonyl)indoline as a white solid (0.148 g, 70% yield).Mass spectrum m/z 288, 290 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.32 (d,J=1.1 Hz, 1H), 7.25-7.17 (m, 2H), 6.94 (dd, J=16.3, 9.9 Hz, 1H),6.32-6.18 (m, 2H), 3.94 (t, J=8.5 Hz, 2H), 3.06 (t, J=8.5 Hz, 2H).

Intermediate 55 N-(3-Bromophenyl)ethenesulfonamide

Following the procedure used to prepare Intermediate 54, 3-bromoanilinewas converted into N-(3-bromophenyl)ethenesulfonamide in 17% yield. ¹HNMR (400 MHz, CDCl₃) δ 7.35-7.29 (m, 2H), 7.20 (t, J=7.9 Hz, 1H),7.13-7.09 (m, 1H), 6.57 (dd, J=16.4, 9.8 Hz, 1H), 6.37-6.31 (m, 2H),6.02 (d, J=9.9 Hz, 1H).

Intermediate 56 N-(3-Bromobenzyl)ethenesulfonamide

Following the procedure used to prepare Intermediate 54, (3-bromophenyl)methanamine was converted into N-(3-bromobenzyl)ethenesulfonamide in 41%yield. Mass spectrum m/z 298, 300 (M+Na)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.50-7.43 (m, 2H), 7.29-7.21 (m, 2H), 6.51 (dd, J=16.5, 9.9 Hz, 1H),6.28 (d, J=16.5 Hz, 1H), 5.96 (d, J=9.9 Hz, 1H), 4.64 (br. s., 1H), 4.20(d, J=6.2 Hz, 2H).

Intermediate 57 N-(2-(3-Bromophenyl)propan-2-yl)ethenesulfonamide

Following the procedure used to prepare Intermediate 54,2-(3-bromophenyl) propan-2-amine was converted intoN-(2-(3-bromophenyl)propan-2-yl)ethenesulfonamide in 74% yield. Massspectrum m/z 326, 328 (M+Na)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (t, J=1.9Hz, 1H), 7.42 (dddd, J=7.9, 4.9, 1.9, 1.0 Hz, 2H), 7.26-7.21 (m, 1H),6.37 (dd, J=16.5, 9.7 Hz, 1H), 6.04 (d, J=16.5 Hz, 1H), 5.72 (d, J=9.7Hz, 1H), 4.64 (s, 1H), 1.73 (s, 6H).

Intermediate 58 1-(3-Bromophenyl)-3-methylenepyrrolidin-2-one

Intermediate 58A: 1-(3-Bromophenyl)pyrrolidin-2-one

A mixture of dihydrofuran-2(3H)-one (1.51 mL, 19.7 mmol), 3-bromoaniline(1.79 mL, 16.5 mmol), and concentrated aqueous HCl (0.70 mL) was heatedat 160° C. After 16 h the mixture was cooled to room temperature.Additional dihydrofuran-2(3H)-one (0.5 mL) was added and heating wasresumed at 160° C. After a total of 36 h the mixture was cooled to roomtemperature and partitioned between water and EtOAc. The organic phasewas washed with brine and concentrated. The residue was subjected tocolumn chromatography on silica gel (40 g), eluting with EtOAc-hexanes(gradient from 40-50%), to provide 1-(3-bromophenyl)pyrrolidin-2-one asa solid (4.16 g, quantitative yield). Mass spectrum m/z 240, 242 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 7.80 (t, J=2.0 Hz, 1H), 7.65-7.60 (m, 1H),7.30-7.27 (m, 1H), 7.26-7.20 (m, 1H), 3.85 (t, J=7.0 Hz, 2H), 2.63 (t,J=8.0 Hz, 2H), 2.23-2.10 (m, 2H).

Intermediate 58B: Ethyl2-(1-(3-bromophenyl)-2-oxopyrrolidin-3-yl)-2-oxoacetate

A stirred mixture of sodium hydride (60% in mineral oil, 1.84 g, 46.0mmol) in THF (43.8 mL) was treated slowly with a solution of1-(3-bromophenyl)pyrrolidin-2-one (4.15 g, 16.4 mmol) and diethyloxalate (4.45 mL, 32.8 mmol) in THF (21.9 mL). The mixture was heated atreflux for 6 h, then cooled to room temperature and stirred for 16 h.Acetic acid (1.03 mL, 18.1 mmol) was added dropwise and the mixture wasstirred at room temperature for 1 h, then was partitioned between EtOAcand water. The pH of the aqueous layer was adjusted to 2-3 with 1 Maqueous HCl and the layers were separated. The organic phase was washedwith brine, dried and concentrated. The residue was subjected to columnchromatography on silica gel (80 g), eluting with EtOAc-hexanes(gradient from 20-30%), to provide a sticky white solid. This wassuspended in EtOAc and the precipitate was collected by filtration toprovide ethyl 2-(1-(3-bromophenyl)-2-oxopyrrolidin-3-yl)-2-oxoacetate asa white solid (1.71 g, 31% yield). Mass spectrum m/z 340, 342 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 8.08-8.05 (m, 1H), 7.67 (dt,J=7.0, 2.2 Hz, 1H), 7.44-7.39 (m, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.97 (t,J=7.0 Hz, 2H), 3.07 (t, J=6.9 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).

Intermediate 58

A suspension of ethyl2-(1-(3-bromophenyl)-2-oxopyrrolidin-3-yl)-2-oxoacetate (1.71 g, 5.03mmol) and diethylamine (1.57 mL, 15.1 mmol) in water (10.1 mL) at 0° C.was treated slowly with a 36.5% aqueous formaldehyde (1.52 mL, 20.1mmol). The mixture was stirred at room temperature for 21 h, forming asticky solid. The supernatant was removed by decantation, and theresidue was subjected to column chromatography on silica gel (24 g),eluting with EtOAc-hexanes (gradient from 20-30%), to provide1-(3-bromophenyl)-3-methylenepyrrolidin-2-one as a white solid (0.497 g,39% yield). Mass spectrum m/z 252, 254 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.92 (t, J=1.9 Hz, 1H), 7.76-7.71 (m, 1H), 7.33-7.29 (m, 1H), 7.28-7.23(m, 1H), 6.19-6.15 (m, 1H), 5.50-5.46 (m, 1H), 3.88-3.81 (m, 2H), 2.92(tt, J=6.9, 2.6 Hz, 2H).

Intermediate 59 Mixture of3-Methylene-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one, and3-Methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrol-2(5H)-one

A mixture of 1-(3-bromophenyl)-3-methylenepyrrolidin-2-one [Intermediate58](0.22 g, 0.873 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.233 g,0.916 mmol), potassium acetate (0.171 g, 1.745 mmol), and PdCl₂(dppf)DCM adduct (0.036 g, 0.044 mmol) in 1,4-dioxane (2.18 mL) was bubbledwith nitrogen for about 2-3 min, then was heated at 90° C. under anitrogen atmosphere. After 2 h, the mixture was cooled to roomtemperature and filtered through CELITE®. The solids were washed withEtOAc, MeOH and acetone, and the combined filtrates were concentrated.The residue was purified by column chromatography on silica gel (12 g),eluting with EtOAc-hexanes (gradient from 20-30%), to provide a mixtureof3-methylene-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-oneand3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrol-2(5H)-oneas a colorless oil. Mass spectrum m/z 300 (M+H)⁺.

Intermediate 60 1-(3-Bromo-2-methylphenyl)-3-methylenepyrrolidin-2-one

Following the procedures used to prepare Intermediate 58,3-bromo-2-methylaniline was converted into1-(3-bromo-2-methylphenyl)-3-methylenepyrrolidin-2-one. Mass spectrumm/z 266, 268 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (dd, J=7.6, 1.7 Hz,1H), 7.19-7.08 (m, 2H), 6.17-6.10 (m, 1H), 5.51-5.43 (m, 1H), 3.76-3.68(m, 2H), 2.98 (tt, J=6.8, 2.6 Hz, 2H), 2.30 (s, 3H).

Intermediate 61N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide

A solution of2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to U.S. Pat. No. 8,084,620, Intermediate 50-1](0.200 g, 0.858 mmol), EDC (0.296 g, 1.54 mmol), HOBT (0.236 g, 1.54mmol), methacrylic acid (0.073 mL, 0.867 mmol), and DIEA (0.420 mL, 2.40mmol) in THF (7.2 mL) and DCM (7.2 mL) was stirred at room temperaturefor 4 days. The mixture was concentrated and subjected to columnchromatography on silica gel (24 g), eluting with EtOAc-hexanes(gradient from 10-30%), to provideN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamideas an off-white solid (0.164 g, 64% yield). Mass spectrum m/z 302(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (s, 1H), 7.50 (dd, J=7.4, 1.4Hz, 1H), 7.34-7.29 (m, 1H), 7.20-7.14 (m, 1H), 5.84 (s, 1H), 5.50-5.47(m, 1H), 2.32 (s, 3H), 1.96 (s, 3H), 1.31 (s, 12H).

Intermediate 62N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohex-1-enecarboxamide

Following the procedure used to prepare Intermediate 61 but substitutingcyclohex-1-enecarboxylic acid for methacrylic acid,2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to U.S. Pat. No. 8,084,620, Intermediate 50-1] wasconverted intoN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohex-1-enecarboxamide in 55% yield. Mass spectrum m/z 342(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 1H), 7.48 (dd, J=7.5, 1.3Hz, 1H), 7.31 (dd, J=7.8, 1.2 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 6.73-6.68(m, 1H), 2.31 (s, 3H), 2.29-2.23 (m, 2H), 2.18 (dd, J=5.9, 2.2 Hz, 2H),1.68-1.54 (m, 4H), 1.30 (s, 12H).

Intermediate 632-Cyano-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

Following the procedure used to prepare Intermediate 61 but substituting2-cyanoacetic acid for methacrylic acid,2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to U.S. Pat. No. 8,084,620, Intermediate 50-1] wasconverted into2-cyano-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamidein 89% yield. Mass spectrum m/z 301 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.68 (s, 1H), 7.52-7.47 (m, 1H), 7.43-7.38 (m, 1H), 7.18 (t, J=7.6 Hz,1H), 3.91 (s, 2H), 2.34 (s, 3H), 1.30 (s, 12H).

Intermediate 641-Cyano-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide

Following the procedure used to prepare Intermediate 61 but substituting1-cyanocyclopropanecarboxylic acid for methacrylic acid,2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to U.S. Pat. No. 8,084,620, Intermediate 50-1] wasconverted into1-cyano-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamidein 60% yield. Mass spectrum m/z 327 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.65 (s, 1H), 7.54 (dd, J=7.5, 1.3 Hz, 1H), 7.30 (dd, J=7.9, 1.3 Hz,1H), 7.22-7.15 (m, 1H), 2.31 (s, 3H), 1.72-1.66 (m, 2H), 1.66-1.60 (m,2H), 1.31 (s, 12H).

Intermediate 65N-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

Intermediate 65A: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

A mixture of 3-bromoaniline (1.00 g, 5.81 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.55 g,6.10 mmol) and potassium acetate (1.14 g, 11.6 mmol) in 1,4-dioxane(14.5 mL) was bubbled with nitrogen for 10 min. The mixture was treatedwith PdCl₂(dppf) DCM adduct (0.114 g, 0.140 mmol) and bubbled withnitrogen for 5 min more. The mixture was heated to reflux for 2.75 h,then cooled to room temperature and filtered through CELITE®. The solidswere washed with EtOAc and THF. The combined filtrates were concentratedand the residue was subjected to column chromatography on silica gel (40g), eluting with EtOAc-hexanes (gradient from 10-25%), to provide3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as an off-whitesolid (1.27 g, quantitative yield). Mass spectrum m/z 220 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.24-7.13 (m, 3H), 6.82-6.77 (m, 1H), 3.64 (br. s.,2H), 1.35 (s, 12H).

Intermediate 65

A solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(0.300 g, 1.37 mmol) and DIEA (0.311 mL, 1.78 mmol) in DCM (9.1 mL) wascooled in an ice-bath and treated with acryloyl chloride (0.117 mL, 1.44mmol). The mixture was stirred at room temperature for 40 min, then wasconcentrated and the residue was subjected to column chromatography onsilica gel (24 g), eluting with EtOAc-hexanes (gradient from 15-40%), toprovide N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide as a white solid (0.292 g, 78% yield). Mass spectrum m/z 270(M+H)⁺.

Intermediate 66N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

Following the procedure used to prepare Intermediate 65,2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to U.S. Pat. No. 8,084,620, Intermediate 50-1] wasconverted intoN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamidein 80% yield. Mass spectrum m/z 288 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.01 (br. s., 1H), 7.64 (d, J=5.9 Hz, 1H), 7.23 (t, J=7.7 Hz, 1H), 7.07(br. s., 1H), 6.48-6.40 (m, 1H), 6.32 (br. s., 1H), 5.78 (d, J=9.5 Hz,1H), 2.49 (s, 3H), 1.36 (s, 12H).

Intermediate 67(E)-N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide

Following the procedure used to prepare Intermediate 65 but substituting(E)-but-2-enoyl chloride for acryloyl chloride,2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to U.S. Pat. No. 8,084,620, Intermediate 50-1] wasconverted into(E)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamidein 85% yield. Mass spectrum m/z 302 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.28 (s, 1H), 7.46 (d, J=7.5 Hz, 2H), 7.15 (t, J=7.7 Hz, 1H), 6.83-6.66(m, 1H), 6.21 (d, J=14.7 Hz, 1H), 2.34 (s, 3H), 1.86 (dd, J=6.9, 1.2 Hz,3H), 1.30 (s, 12H).

Intermediate 683-Methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide

Following the procedure used to prepare Intermediate 65 but substituting3-methylbut-2-enoyl chloride for acryloyl chloride,2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to U.S. Pat. No. 8,084,620, Intermediate 50-1] wasconverted into3-methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamidein 85% yield. Mass spectrum m/z 316 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.14 (s, 1H), 7.44 (d, J=7.3 Hz, 2H), 7.14 (t, J=7.6 Hz, 1H), 5.95 (br.s., 1H), 2.33 (s, 3H), 2.12 (d, J=1.1 Hz, 3H), 1.86 (s, 3H), 1.30 (s,12H).

Intermediate 69N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide

Following the procedure used to prepare Intermediate 65 but substitutingcyclopropanecarbonyl chloride for acryloyl chloride,2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to U.S. Pat. No. 8,084,620, Intermediate 50-1] wasconverted intoN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamidein 71% yield. Mass spectrum m/z 302 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.50 (br. s., 1H), 7.43 (dd, J=10.0, 7.8 Hz, 2H), 7.13 (t, J=7.6 Hz,1H), 2.35 (s, 3H), 1.87 (d, J=6.6 Hz, 1H), 1.30 (s, 12H), 0.79-0.74 (m,4H).

Intermediate 70N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionamide

Following the procedure used to prepare Intermediate 65 but substitutingpropionic anhydride for acryloyl chloride,2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to U.S. Pat. No. 8,084,620, Intermediate 50-1] wasconverted intoN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionamide in 88% yield. Mass spectrum m/z 290 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 9.21 (s, 1H), 7.52-7.34 (m, 2H), 7.14 (t, J=7.6 Hz,1H), 2.37-2.30 (m, 5H), 1.30 (s, 12H), 1.10 (t, J=7.6 Hz, 3H).

Intermediate 71(E)-4-(Dimethylamino)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide

A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (0.300g, 1.81 mmol) and a catalytic amount of DMF (7 μL, 0.091 mmol) in THF(22.6 mL) was cooled to 0° C. Oxalyl chloride (0.153 mL, 1.81 mmol) wasadded dropwise and the mixture was warmed to room temperature andstirred for 2 h, then was heated at 50° C. for 30 min. The solution wascooled at 0° C., treated sequentially with DIEA (0.633 mL, 3.62 mmol)and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to the procedure of U.S. Pat. No. 8,084,620,Intermediate 50-1] (0.380 g, 1.63 mmol), and the resulting mixture wasstirred at room temperature. After 30 min, the mixture was partitionedbetween saturated aqueous NaHCO₃ and EtOAc. The organic phase was washedwith brine, dried and concentrated. The residue was subjected to columnchromatography on silica gel (24 g), eluting with EtOAc containingincreasing amounts of 2 M NH₃ in MeOH (sequentially 0%, 5% and 10%), toprovide(E)-4-(dimethylamino)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide as a brown syrup (88 mg, 14% yield). Mass spectrum m/z 345(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 7.53-7.42 (m, 2H),7.15 (t, J=7.6 Hz, 1H), 6.70 (dt, J=15.4, 5.9 Hz, 1H), 6.35 (d, J=15.2Hz, 1H), 3.05 (d, J=5.3 Hz, 2H), 2.34 (s, 3H), 2.17 (s, 6H), 1.30 (s,12H).

Intermediate 72N-Methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

Intermediate 72A:N,2-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

A mixture of 3-bromo-N,2-dimethylaniline (1.90 g, 9.50 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.53 g,9.97 mmol) and potassium acetate (1.86 g, 19.0 mmol) in 1,4-dioxane(23.7 mL) was bubbled with nitrogen for 10 min. The mixture was treatedwith PdCl₂(dppf) DCM adduct (0.194 g, 0.237 mmol) and the mixture wasbubbled with nitrogen for another 5 min, then was heated at reflux.After 2.75 h, the mixture was cooled to room temperature, filteredthrough CELITE®, and the solids were washed with EtOAc. The combinedfiltrates were concentrated and the residue was subjected to columnchromatography on silica gel (40 g), eluting with EtOAc-hexanes(gradient from 5-15%), to provideN,2-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline asan off-white waxy solid (2.26 g, 96% yield). Mass spectrum m/z 249(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.12 (m, 2H), 6.72 (dd, J=6.5,2.8 Hz, 1H), 3.63 (br. s., 1H), 2.90 (s, 3H), 2.36 (s, 3H), 1.35 (s,12H).

Intermediate 72

Following the procedure used to prepare Intermediate 51,N,2-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline wasconverted intoN-methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamideas a white solid in 98% yield. Mass spectrum m/z 302 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.77 (dd, J=7.3, 1.3 Hz, 1H), 7.25-7.16 (m, 2H), 6.37 (dd,J=16.8, 2.1 Hz, 1H), 5.90 (dd, J=16.9, 10.3 Hz, 1H), 5.47 (dd, J=10.3,2.2 Hz, 1H), 3.25 (s, 3H), 2.38 (s, 3H), 1.37 (s, 12H).

Intermediate 73N-Methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

Intermediate 73A:N-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Following the procedure used in the preparation of Intermediate 72A,3-bromo-N-methylaniline was converted intoN-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline inquantitative yield. Mass spectrum m/z 234 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.25-7.15 (m, 2H), 7.07 (d, J=2.4 Hz, 1H), 6.73 (ddd, J=7.7,2.6, 1.3 Hz, 1H), 4.02-3.43 (b, 1H), 2.87 (s, 3H), 1.35 (s, 12H).

Intermediate 73

Following the procedure used in the preparation of Intermediate 72,N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline wasconverted intoN-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamidein 88% yield. Mass spectrum m/z 288 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.77 (d, J=7.3 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H),7.26-7.23 (m, 1H), 6.37 (dd, J=16.7, 2.0 Hz, 1H), 6.06 (dd, J=16.7, 10.6Hz, 1H), 5.51 (dd, J=10.3, 2.0 Hz, 1H), 3.36 (s, 3H), 1.36 (s, 12H).

Intermediate 74N-(2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methylacrylamide

Intermediate 74A: 2 N-(3-Bromo-2-methylphenyl)formamide

A solution of 3-bromo-2-fluoroaniline (1.00 g, 5.26 mmol) in formic acid(1.99 mL, 52.6 mmol) was heated at 90° C. for 16 h. The mixture wascooled to room temperature and partitioned between EtOAc and water. Theorganic phase was washed sequentially with saturated aqueous NaHCO₃ andbrine, dried and concentrated to provideN-(3-bromo-2-fluorophenyl)formamide as a beige solid (1.02 g, 89%yield). Mass spectrum m/z 218, 220 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.50 (s, 1H), 8.40-8.17 (m, 1H), 7.53-7.41 (m, 1H), 7.31 (ddd, J=8.0,6.6, 1.4 Hz, 1H), 7.05 (td, J=8.2, 1.4 Hz, 1H).

Intermediate 74B: 3-Bromo-2-fluoro-N-methylaniline

A solution of N-(3-bromo-2-fluorophenyl)formamide (1.00 g, 4.59 mmol) inTHF (15 mL) was cooled to 0° C., treated dropwise with borane-methylsulfide complex (6.88 mL, 13.8 mmol) and heated at 70° C. for 2 h. Themixture was cooled to room temperature and treated with MeOH, stirred atroom temperature for 30 min, then was treated slowly with 1 M aqueousHCl. The mixture was heated to 70° C. for 1 h, then was cooled to roomtemperature, treated with 1 M aqueous NaOH and extracted with EtOAc. Theorganic extract was washed with brine, dried and concentrated. Theresidue was subjected to column chromatography on silica gel, elutingwith EtOAc-hexanes, to provide 3-bromo-2-fluoro-N-methylaniline as acolorless oil (0.800 g, 85% yield). Mass spectrum m/z 204, 206 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 6.92-6.86 (m, 1H), 6.84-6.78 (m, 1H),6.63-6.56 (m, 1H), 4.03 (br. s., 1H), 2.88 (d, J=4.6 Hz, 3H).

Intermediate 74C:2-Fluoro-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Following the procedure used in the preparation of Intermediate 72A,3-bromo-2-fluoro-N-methylaniline was converted into2-fluoro-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilinein 71% yield. Mass spectrum m/z 252 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.02 (d, J=7.3 Hz, 2H), 6.85-6.73 (m, 1H), 4.07-3.85 (m, 1H), 2.86 (s,3H), 1.38-1.32 (m, 12H).

Intermediate 74

Following the procedure used in the preparation of Intermediate 72,2-fluoro-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilinewas converted intoN-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methylacrylamidein 56% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.74 (s, 1H), 7.33-7.27 (m, 1H),7.22-7.06 (m, 1H), 6.37 (d, J=16.7 Hz, 1H), 6.16-5.87 (m, 1H), 5.52 (d,J=10.1 Hz, 1H), 3.30 (s, 3H), 1.38 (s, 12H).

Intermediate 75N-Methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide

A solution ofN,2-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[Intermediate 72A] (0.500 g, 2.02 mmol) in DCM (10.1 mL), cooled to 0°C., was treated with DIEA (0.530 mL, 3.03 mmol), then2-chloroethanesulfonyl chloride (0.254 mL, 2.43 mmol) was addeddropwise. The mixture was stirred at room temperature for 3 h, then wasconcentrated. The residue was subjected to column chromatography onsilica gel (24 g), eluting with EtOAc-hexanes (gradient from 10-20%), toprovideN-methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamideas a white waxy solid (0.432 g, 63% yield). Mass spectrum m/z 338(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (dd, J=7.3, 1.3 Hz, 1H),7.27-7.23 (m, 1H), 7.21-7.15 (m, 1H), 6.62 (dd, J=16.5, 9.9 Hz, 1H),6.23 (d, J=16.7 Hz, 1H), 6.02 (d, J=9.9 Hz, 1H), 3.15 (s, 3H), 2.61 (s,3H), 1.35 (s, 12H).

Intermediate 76N-Methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide

Following the procedure used to prepare Intermediate 75,N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[Intermediate 73A] was converted intoN-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamidein 61% yield. Mass spectrum m/z 324 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ7.62-7.54 (m, 2H), 7.51-7.37 (m, 2H), 6.86 (dd, J=16.4, 10.0 Hz, 1H),6.14 (d, J=10.1 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 3.18 (s, 3H), 1.30 (s,12H).

Intermediate 77N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide

Following the procedure used to prepare Intermediate 75,2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[prepared according to the procedure of U.S. Pat. No. 8,084,620,Intermediate 46-1, Step 1] was converted intoN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamidein 49% yield. Mass spectrum m/z 324 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.24 (s, 1H), 7.52-7.47 (m, 1H), 7.27 (d, J=6.6 Hz, 1H), 7.19-7.13 (m,1H), 6.83 (dd, J=16.5, 9.9 Hz, 1H), 5.99-5.89 (m, 2H), 2.44 (s, 3H),1.30 (s, 12H).

Intermediate 78N-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide

Following the procedure used to prepare Intermediate 75,3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [Intermediate65A] was converted intoN-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamidein 40% yield. Mass spectrum m/z 310 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.63 (d, J=7.0 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.44-7.40 (m, 1H),7.40-7.34 (m, 1H), 6.57 (dd, J=16.5, 9.9 Hz, 1H), 6.34-6.26 (m, 2H),5.97 (d, J=9.9 Hz, 1H), 1.36 (s, 12H).

Intermediate 794,4,5,5-Tetramethyl-2-(3-(vinylsulfonyl)phenyl)-1,3,2-dioxaborolane

Intermediate 79A: (3-Bromophenyl)(2-chloroethyl)sulfane

A mixture of 3-bromobenzenethiol (1.09 mL, 10.6 mmol),1-bromo-2-chloroethane (1.76 mL, 21.2 mmol) and K₂CO₃ (1.46 g, 10.6mmol) in DMF (10.6 mL) was heated at 60° C. for 5 h. The mixture wascooled to room temperature and stirred overnight. After 16 h, themixture was partitioned between water and ether. The organic phase waswashed with brine, dried and concentrated to provide(3-bromophenyl)(2-chloroethyl)sulfane as a colorless oil (2.63 g, 99%yield), used without further purification. ¹H NMR (400 MHz, CDCl₃) δ7.53 (t, J=1.8 Hz, 1H), 7.38 (ddd, J=8.0, 1.8, 1.0 Hz, 1H), 7.31 (ddd,J=7.8, 1.8, 1.0 Hz, 1H), 7.22-7.15 (m, 1H), 3.65-3.60 (m, 2H), 3.27-3.22(m, 2H).

Intermediate 79B: 1-Bromo-3-((2-chloroethyl)sulfonyl)benzene

A solution of (3-bromophenyl)(2-chloroethyl)sulfane (2.63 g, 10.5 mmol)in DCM (10.5 mL) was cooled to 0° C. and treated portionwise with asolution of m-chloroperoxybenzoic acid (6.01 g, 26.1 mmol) in DCM (40mL). The resulting suspension was stirred at 0° C. for 4 h. The mixturewas diluted with DCM, treated with saturated aqueous NaHCO₃ and sodiumthiosulfate. The organic phase was separated, washed with brine, driedand concentrated. The residue was subjected to column chromatography onsilica gel (40 g), eluting with EtOAc-hexanes (gradient from 5-30%), toprovide 1-bromo-3-((2-chloroethyl)sulfonyl)benzene as a white solid(2.93 g, 99% yield). Mass spectrum m/z 283, 285 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.08 (t, J=1.9 Hz, 1H), 7.86 (dddd, J=14.5, 7.9, 1.8, 1.1 Hz,2H), 7.49 (t, J=7.9 Hz, 1H), 3.81-3.76 (m, 2H), 3.59-3.52 (m, 2H).

Intermediate 79

A mixture of 1-bromo-3-((2-chloroethyl)sulfonyl)benzene (0.500 g, 1.76mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.470 g, 1.85 mmol), potassium acetate (0.346 g, 3.53 mmol) andPdCl₂(dppf) DCM adduct (0.036 g, 0.044 mmol) in 1,4-dioxane (4.41 mL)was bubbled with nitrogen for about 2-3 min, then was heated at reflux.After 2.5 h, the mixture was cooled to room temperature and filteredthrough CELITE®. The solids were washed with EtOAc, and the combinedfiltrates were concentrated. The residue was subjected to columnchromatography on silica gel (24 g), eluting with EtOAc-hexanes(gradient from 10-25%), to provide4,4,5,5-tetramethyl-2-(3-(vinylsulfonyl)phenyl)-1,3,2-dioxaborolane as alight yellow waxy solid (0.196 g, 80% purity, 30% yield), used withoutfurther purification. Mass spectrum m/z 295 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.33 (s, 1H), 8.09-8.02 (m, 1H), 8.01-7.95 (m, 1H), 7.60-7.51(m, 1H), 6.73-6.63 (m, 1H), 6.48 (d, J=16.5 Hz, 1H), 6.04 (d, J=9.7 Hz,1H), 1.36 (s, 12H).

Intermediate 80N-(Cyanomethyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Intermediate 80A: 3-Bromo-N-(cyanomethyl)-2-methylbenzamide

A solution of 3-bromo-2-methylbenzoic acid (0.500 g, 2.33 mmol), EDC(0.669 g, 3.49 mmol), HOBT (0.534 g, 3.49 mmol), and DIEA (1.22 mL, 6.98mmol) in THF (14.5 mL) and DCM (14.5 mL) was stirred at room temperaturefor 30 min, then was treated with 2-aminoacetonitrile hydrochloride(0.237 g, 2.56 mmol). The mixture was stirred at room temperature for 5h, then was partitioned between saturated aqueous NaHCO₃ and EtOAc. Theorganic phase was dried and concentrated, and the residue was purifiedby column chromatography on silica gel (24 g), eluting withEtOAc-hexanes (gradient from 20-40%) to provide3-bromo-N-(cyanomethyl)-2-methylbenzamide as a white solid (0.554 g, 94%yield). Mass spectrum m/z 253, 255 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.67 (dd, J=8.0, 1.0 Hz, 1H), 7.30 (dd, J=7.7, 0.9 Hz, 1H), 7.14-7.08(m, 1H), 6.14 (br. s., 1H), 4.38 (d, J=5.9 Hz, 2H), 2.48 (s, 3H).

Intermediate 80

Following the procedure used to prepare Intermediate 65A,3-bromo-N-(cyanomethyl)-2-methylbenzamide was converted intoN-(cyanomethyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamideas a yellow solid in 91% yield. Mass spectrum m/z 301 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.96 (t, J=5.6 Hz, 1H), 7.69 (dd, J=7.5, 1.5 Hz,1H), 7.37 (dd, J=7.6, 1.4 Hz, 1H), 7.30-7.18 (m, 1H), 4.28 (d, J=5.5 Hz,2H), 2.45 (s, 3H), 1.31 (s, 12H).

Intermediate 818-Fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Intermediate 81A: 2-Amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide

A solution of 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2.00 g, 11.0mmol) and 3-bromo-2-methylaniline (4.11 g, 22.1 mmol) in 1,4-dioxane (20mL) in a sealed reaction vessel was heated at 110° C. for 4 days. Themixture was cooled to room temperature and treated with 10% aqueousK₂CO₃ and stirred for 30 min. The mixture was extracted three times withDCM, and the combined organic phases were washed with water, dried andconcentrated. The residue was triturated with ether, and the precipitatewas collected by filtration to give a gray solid (2.50 g). The filtratewas concentrated and the residue was again triturated with ether to givea gray solid (230 mg). The two solids were combined to provide2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide as a gray solid(2.73 g, 78% yield). Mass spectrum m/z 323, 325 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.69 (d, J=7.9 Hz, 1H), 7.65 (br. s., 1H), 7.50-7.46 (m, 1H),7.32 (d, J=8.1 Hz, 1H), 7.19-7.11 (m, 2H), 6.73-6.64 (m, 1H), 5.69 (br.s., 2H), 2.44 (s, 3H).

Alternative Synthesis of2-Amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide

A suspension of 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (3.00 g, 16.6mmol) in xylenes (50 mL) was treated with 3-bromo-2-methylaniline (3.08g, 16.6 mmol) and heated to reflux. After 6 h the mixture was allowed tocool to room temperature overnight. The resulting suspension was dilutedwith hexanes and the precipitate was collected by filtration, rinsedwith hexanes and air-dried to provide2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide as a white solid(4.50 g, 84% yield).

Intermediate 81B:3-(3-Bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione

A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide (5.70g, 17.6 mmol) in THF (100 mL) was treated with bis(trichloromethyl)carbonate [triphosgene] (6.28 g, 21.2 mmol) at room temperature andstirred for 15 min. The mixture was diluted with EtOAc, carefullytreated with saturated aqueous NaHCO₃ and stirred at room temperatureuntil gas evolution stopped. The organic phase was separated and washedsequentially with saturated aqueous NaHCO₃, water and brine, and wasdried and concentrated. The residue was triturated with ether to provide3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as anoff-white solid (6.00 g, 97% yield). Mass spectrum m/z 349, 351 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J=17.6 Hz, 1H), 7.99 (d, J=8.1 Hz,1H), 7.70 (dd, J=7.8, 1.2 Hz, 1H), 7.54-7.43 (m, 1H), 7.28-7.21 (m, 2H),7.21-7.17 (m, 1H), 2.28 (s, 3H).

Intermediate 81C:3-(3-Bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione

A solution of3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione (4.80 g,13.8 mmol) in DMF (25 mL) was treated with Cs₂CO₃ (13.4 g, 41.2 mmol).The suspension was stirred at room temperature and treated quicklydropwise with iodomethane (4.30 mL, 68.7 mmol) and stirred rapidly atroom temperature for 1 h. The mixture was diluted with EtOAc and water(200 mL). The organic phase was separated and washed sequentially withwater and brine, then was dried and concentrated to provide3-(3-bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dioneas a tan glassy solid (4.80 g, 96% yield). Mass spectrum m/z 363, 365(M+H)⁺.

Intermediate 81

A mixture of3-(3-bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione(4.80 g, 13.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.36 g,17.2 mmol), potassium acetate (3.89 g, 39.6 mmol) and PdCl₂(dppf) DCMadduct (0.540 g, 0.661 mmol) in 1,4-dioxane (65 mL) was heated to refluxfor 2 h. After cooling to room temperature, the mixture was filteredthrough CELITE® and the solids were rinsed with EtOAc. The filtrate wasdiluted with EtOAc, washed with water, and dried and concentrated. Theresidue was subjected to column chromatography on silica gel (80 g),eluting with EtOAc-hexanes (gradient from 20-50%), to provide8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dioneas a white solid (4.61 g, 85% yield). Mass spectrum m/z 411 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.14-8.08 (m, 1H), 7.93 (dd, J=7.5, 1.3 Hz, 1H),7.48 (ddd, J=14.0, 8.0, 1.5 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.27-7.20(m, 2H), 3.88 (d, J=7.9 Hz, 3H), 2.36 (s, 3H), 1.36 (s, 12H).

Intermediate 821-Methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Intermediate 82A: 2-Amino-N-(3-bromo-2-methylphenyl)benzamide

A solution of 2-aminobenzoic acid (5.00 g, 36.5 mmol)and thionylchloride (8.68 g, 72.9 mmol) in toluene (50 mL) was heated at reflux for60 min. The mixture was concentrated and the residue was suspended inTHF (50 mL), cooled in an ice-water bath and treated with3-bromo-2-methylaniline (20.35 g, 109 mmol). The resulting suspensionwas heated at reflux for 2 h. The mixture was cooled to room temperatureand treated with 10% aqueous K₂CO₃ (50 mL), stirred vigorously for 15mi, and extracted with EtOAc. The organic phase was dried andconcentrated. The residue was purified by column chromatography onsilica gel to give 2-amino-N-(3-bromo-2-methylphenyl) benzamide asalight yellow solid (4.70 g, 42% yield). Mass spectrum mz 305, 307(M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.72 (d, J=7.9 Hz, 1H), 7.67 (br. s.,1H), 7.54 (dd, J=8.3, 1.2 Hz, 1H), 7.48 (dd, J=7.9, 0.9 Hz, 1H),7.36-7.31 (n, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.81-6.73 (m, 2H), 5.59 (br.s., 2H), 2.45 (s, 3H).

Alternative Synthesis of 2-Amino-N-(3-bromo-2-methylphenyl)benzamide

A suspension of 1H-benzo[d][1,3]oxazine-2,4-dione (5.00 g, 30.7 mmol)and 3-bromo-2-methylaniline (5.70 g, 30.7 mmol) in xylenes (50 mL) washeated at reflux for 8 h. The solvent was removed by distillation andthe residue was purified by column chromatography on silica g), elutingwith EtOAc-hexanes (gradient from 0-50%), to give2-amino-N-(3-bromo-2-methylphenyl)benzamide as an off-white solid (2.30g, 24% yield).

Intermediate 82B: 3-(3-Bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione

A solution of 2-amino-N-(3-bromo-2-methylphenyl)benzamide (2.00 g, 6.55mmol) in THF (50 mL) was treated with bis(trichloromethyl) carbonate[triphosgene](2.92 g, 9.83 mmol) and heated at reflux for 60 min. Themixture was cooled to room temperature and treated with saturatedaqueous NaHCO₃, extracted with EtOAc, and the combined organic phaseswere washed twice with saturated NaHCO₃, then with water, dried andconcentrated. The residue was triturated with DCM to give a white solidwhich was collected by filtration. The residue from concentration of thefiltrate was triturated with DCM to give additional white solid whichwas collected by filtration. The two solids were combined to give3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione as a white solid(2.10 g, 97% yield). Mass spectrum m/z 331, 333 (M+H)⁺. ¹H NMR (400 MHz,MeOH-d₄) δ 8.07 (dd, J=7.92, 1.32 Hz, 1H), 7.65-7.75 (m, 2H), 7.21-7.32(m, 4H), 2.20 (s, 3H). ¹H NMR (400 MHz, CDCl₃) δ 9.38 (br. s., 1H), 8.19(dd, J=7.9, 1.1 Hz, 1H), 7.76-7.69 (m, 1H), 7.69-7.60 (m, 1H), 7.35-7.17(m, 3H), 7.04-6.97 (m, 1H), 2.28 (s, 3H).

Intermediate 82C:3-(3-Bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione

A suspension of 3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione(23.02 g, 69.5 mmol) and Cs₂CO₃ (34.0 g, 104 mmol) in DMF (70 mL) cooledin an ice-water bath was treated portionwise with iodomethane (5.22 mL,83 mmol). The mixture was warmed to room temperature and stirred for 30min. The mixture was filtered and the filtrate was concentrated. Theresidue was partitioned between EtOAc and water, forming a precipitatewhich was collected by filtration. The collected solid was washed withwater and dried overnight under vacuum to give a white solid. Theorganic phase of the filtrate was separated, washed three times with 10%aqueous LiCl, then was washed twice with water, dried and concentratedto give additional solid. The two solids were combined to give3-(3-bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione as awhite solid (15.56 g, 92% yield). Mass spectrum m/z 345, 347 (M+H)⁺.

Intermediate 82

A mixture of3-(3-bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione (36.39g, 105 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (40.2 g, 158mmol), PdCl₂(dppf) DCM adduct (4.30 g, 5.27 mmol) and potassium acetate(31.0 g, 316 mmol) in 1,4-dioxane (500 mL) and DMSO (50 mL) was heatedat reflux for 24 h. Additional PdCl₂(dppf) DCM adduct (1.47 g) was addedand the mixture was heated at reflux for 6 h more. The cooled mixturewas filtered through CELITE® and the filtrate was concentrated. Theresidue was diluted with EtOAc, shaken with water, and both phases werefiltered through CELITE® to remove a black precipitate. The organicphase of the filtrate was separated, washed sequentially with water andbrine, dried and concentrated. The residue was purified by columnchromatography on silica gel (2 330 g columns), eluting withEtOAc-hexanes (gradient from 20-100%). The residue from concentration ofthe product-containing effluent was triturated with EtOAc to give asolid which was collected by filtration. The filtrate was concentratedand crystallized from EtOAc to give additional solid. The mother liquorfrom this crystallization was concentrated and the residue was purifiedby column chromatography on silica gel (330 g), eluting withEtOAc-hexanes (gradient from 20-50%), to give additional solid. Thethree solids were combined to give1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dioneas a white solid (21.2 g, 51% yield). Mass spectrum m/z 393 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.35 (d, J=7.9 Hz, 1H), 7.64 (ddd, J=8.5, 7.3,1.5 Hz, 1H), 7.59 (dd, J=7.4, 1.4 Hz, 1H), 7.33-7.27 (m, 1H), 7.24-7.17(m, 1H), 7.12 (d, J=8.1 Hz, 2H), 3.55 (s, 3H), 1.59 (s, 3H), 1.39 (s,12H).

Intermediate 835-Fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide

Following the procedure used to prepare Intermediate 9,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 2]was converted into5-fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamidein 38% yield. Mass spectrum m/z 333 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ7.27 (d, J=10.1 Hz, 1H), 2.39 (s, 3H), 2.24 (s, 3H), 1.44 (s, 12H).

Intermediate 84(RS)-5-Fluoro-2,3-dimethyl-4-(2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 48,9-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine [prepared according toprocedures described in Example 13 of PCT Publication No. WO2012/149236] was converted into(RS)-5-fluoro-2,3-dimethyl-4-(2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-1H-indole-7-carboxamide.Mass spectrum m/z 354 (M+H)⁺.

Intermediate 85(RS)-5-Fluoro-4-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamideTFA Salt

Intermediate 85A: Ethyl 2-bromo-4-fluorophenethylcarbamate

A mixture of 3-(2-bromo-4-fluorophenyl)propanoic acid (2.00 g, 8.10mmol), EtOH (0.945 mL, 16.2 mmol), TEA (3.38 mL, 24.3 mmol) anddiphenylphosphoryl azide (2.45 g, 8.90 mmol) in anhydrous THF (20 mL)was heated at 80° C. for 18 h. The mixture was concentrated and theresidue was subjected to column chromatography on silica gel, elutingwith EtOAc-hexanes (gradient from 0-100%) to provide ethyl2-bromo-4-fluorophenethylcarbamate as a colorless gum (2.03 g, 82%yield). Mass spectrum m/z 290, 292 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.31 (dd, J=8.3, 2.5 Hz, 1H), 7.24-7.16 (m, 1H), 6.99 (td, J=8.3, 2.6Hz, 1H), 4.68 (br. s., 1H), 4.19-4.06 (m, 2H), 3.43 (q, J=6.6 Hz, 2H),2.95 (t, J=6.9 Hz, 2H), 1.30-1.19 (m, 3H).

Intermediate 85B: Ethyl5-bromo-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

A solution of ethyl 2-bromo-4-fluorophenethylcarbamate (1.30 g, 4.48mmol) in acetic acid (9.00 mL, 157 mmol) and sulfuric acid (3.00 mL,56.3 mmol) was stirred at 0° C. and treated with paraformaldehyde (0.148g, 4.93 mmol). The mixture was stirred at room temperature for threedays, then was diluted with water (50 mL) and was extracted with EtOAc.The organic layer was washed sequentially with saturated aqueous NaHCO₃and 1 M aqueous M HCl, dried and concentrated. The residue was subjectedto column chromatography on silica gel, eluting with EtOAc-hexanes(gradient from 0-30%) to provide ethyl5-bromo-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate as a whitesolid (334 mg, 23% yield). Mass spectrum m/z 302, 304 (M+H)⁺.

Intermediate 85C: 5-Bromo-7-fluoro-1,2,3,4-tetrahydroisoquinoline

A solution of ethyl5-bromo-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (350 mg, 1.16mmol) in ethylene glycol (7.0 mL) was treated with a solution of KOH(5.85 g, 104 mmol) in water (5.6 mL) and the mixture was stirred at 90°C. for 18 h. The mixture was cooled to room temperature, diluted withwater (30 mL) and extracted with EtOAc (50 mL). The organic layer wasdried and concentrated to provide5-bromo-7-fluoro-1,2,3,4-tetrahydroisoquinoline, used without furtherpurification. Mass spectrum m/z 230, 232 (M+H)⁺.

Intermediate 85

Following the procedures used to prepare Intermediate 48,5-bromo-7-fluoro-1,2,3,4-tetrahydroisoquinoline was converted into(RS)-5-fluoro-4-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide,TFA salt. Mass spectrum m/z 356 (M+H)⁺.

Intermediate 865-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 48,6-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride was converted into5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-indole-7-carboxamide,TFA salt. Mass spectrum m/z 338 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 7.42(d, J=10.6 Hz, 1H), 7.37-7.27 (m, 3H), 4.48 (s, 2H), 3.59 (td, J=6.4,2.3 Hz, 2H), 3.25-3.18 (m, 2H), 2.36 (s, 3H), 1.65 (s, 3H).

Intermediate 87(RS)-5-Fluoro-4-(indolin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide TFASalt

Following the procedures used to prepare Intermediate 48,4-bromoindoline was converted into(RS)-5-fluoro-4-(indolin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide TFAsalt. Mass spectrum m/z 324 (M+H)⁺.

Intermediate 88(RS)-4-(3,4-Dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 48,8-bromo-3,4-dihydro-2H-benzo[b][1,4]thiazine [prepared according toprocedures described in Example 331 of PCT Publication No. WO2012/149236] was converted into(RS)-4-(3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamideTFA salt. Mass spectrum m/z 356 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 7.38(d, J=10.4 Hz, 1H), 7.11-7.02 (m, 1H), 6.87 (dd, J=8.1, 1.3 Hz, 1H),6.76 (dd, J=7.4, 1.2 Hz, 1H), 3.63 (dtd, J=8.1, 6.0, 1.9 Hz, 2H), 3.05(dt, J=6.6, 4.0 Hz, 2H), 2.35 (s, 3H), 1.67 (s, 3H).

Intermediate 89(S)-4-(3-(Cyclopropylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Intermediate 89A: (S)-tert-Butyl3-(cyclopropylamino)piperidine-1-carboxylate

A solution of (S)-tert-butyl 3-aminopiperidine-1-carboxylate (1.00 g,4.99 mmol), (1-ethoxycyclopropoxy)trimethylsilane (0.870 g, 4.99 mmol)and acetic acid (2.86 mL, 49.9 mmol) in MeOH (15 mL) was treated withsodium cyanoborohydride (0.471 g, 7.49 mmol) and the mixture was stirredat 60° C. for 14 h. The mixture was cooled to room temperature, dilutedwith EtOAc, washed with saturated aqueous NaHCO₃, dried andconcentrated. The residue was subjected to column chromatography onsilica gel, eluting with EtOAc-hexanes (gradient from 0-100%) to provide(S)-tert-butyl 3-(cyclopropylamino)piperidine-1-carboxylate as acolorless oil (180 mg, 15% yield). Mass spectrum m/z 241 (M+H)⁺. ¹H NMR(400 MHz, MeOH-d₄) δ 4.19-4.09 (m, 1H), 3.84 (d, J=12.8 Hz, 1H), 2.83(ddd, J=13.5, 10.9, 3.1 Hz, 1H), 2.71-2.60 (m, 2H), 2.18 (tt, J=7.0, 3.6Hz, 1H), 2.05-1.96 (m, 1H), 1.75-1.66 (m, 1H), 1.52-1.40 (m, 11H),1.37-1.27 (m, 1H), 0.53-0.47 (m, 2H), 0.38-0.33 (m, 2H).

Intermediate 89B: (S)-tert-Butyl3-(((benzyloxy)carbonyl)(cyclopropyl)amino)piperidine-1-carboxylate

A solution of (S)-tert-butyl3-(cyclopropylamino)piperidine-1-carboxylate (180 mg, 0.749 mmol) andbenzyl (2,5-dioxopyrrolidin-1-yl) carbonate (560 mg, 2.25 mmol) in THF(2 mL) was treated with TEA (313 μL, 2.25 mmol) and the mixture wasstirred at room temperature for 14 h. The mixture was diluted withEtOAc, washed with saturated aqueous NaHCO₃, dried and concentrated. Theresidue was subjected to column chromatography on silica gel, elutingwith EtOAc-hexanes (gradient from 0-100%), then was purified by followedby preparative reverse-phase HPLC to provide (S)-tert-butyl3-(((benzyloxy)carbonyl)(cyclopropyl)amino)piperidine-1-carboxylate as acolorless viscous oil (200 mg, 71% yield). ¹H NMR (400 MHz, MeOH-d₄) δ7.44-7.26 (m, 5H), 5.12 (s, 2H), 4.00 (d, J=11.4 Hz, 2H), 3.62-3.45 (m,1H), 3.10 (t, J=11.9 Hz, 1H), 2.72-2.50 (m, 2H), 2.10 (qd, J=12.5, 3.9Hz, 1H), 1.89 (d, J=11.7 Hz, 1H), 1.74 (d, J=13.6 Hz, 1H), 1.55-1.38 (m,10H), 0.90-0.77 (m, 2H), 0.74-0.61 (m, 2H).

Intermediate 89C: (S)-Benzyl cyclopropyl(piperidin-3-yl)carbamate

A solution of (S)-tert-butyl3-(((benzyloxy)carbonyl)(cyclopropyl)amino)-piperidine-1-carboxylate(200 mg, 0.534 mmol) in DCM (1 mL) was treated with TFA (0.50 mL, 6.49mmol) and the mixture was allowed to stand at room temperature for 30min. The solution was concentrated and the residue was dissolved in DCM,washed with saturated aqueous NaHCO₃, dried and concentrated to provide(S)-benzyl cyclopropyl(piperidin-3-yl)carbamate as a colorless oil (140mg, 96% yield). Mass spectrum m/z 275 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄)δ 7.43-7.16 (m, 5H), 5.11 (s, 2H), 3.66 (dtd, J=11.7, 7.9, 4.0 Hz, 1H),2.96-2.86 (m, 3H), 2.56-2.49 (m, 1H), 2.41 (td, J=12.7, 2.9 Hz, 1H),2.10-1.98 (m, 1H), 1.87 (dd, J=12.3, 3.1 Hz, 1H), 1.81-1.72 (m, 1H),1.60-1.46 (m, 1H), 0.83-0.76 (m, 2H), 0.70-0.62 (m, 2H).

Intermediate 89

Following the procedures used to prepare Intermediate 13, (S)-benzylcyclopropyl(piperidin-3-yl)carbamate and4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]were converted into(S)-4-(3-(cyclopropylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide.Mass spectrum m/z 345 (M+H)⁺.

Intermediate 905-Fluoro-2,3-dimethyl-4-(piperazin-1-yl)-1H-indole-7-carboxamide

Intermediate 90A: tert-Butyl4-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperazine-1-carboxylate

A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile[Intermediate 12] (0.200 g, 0.749 mmol), tert-butylpiperazine-1-carboxylate (0.146 g, 0.786 mmol), Cs₂CO₃ (0.488 g, 1.50mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.023 g, 0.037mmol), and tris(dibenzylideneacetone)dipalladium (0.034 g, 0.037 mmol)in 1,4-dioxane (5 mL) was bubbled with nitrogen and heated overnight at95° C. The mixture was cooled to room temperature, filtered throughCELITE® and concentrated. The residue was subjected to columnchromatography on silica gel, eluting with EtOAc-hexanes (gradient from0-100%), to provide tert-butyl4-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperazine-1-carboxylateas a yellow solid (0.194 g, 70% yield). Mass spectrum m/z 373 (M+H)⁺.

Intermediate 90

A mixture of tert-butyl4-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperazine-1-carboxylate(0.195 g, 0.524 mmol), chlorotrimethylsilane (5.00 mL, 39.1 mmol), andwater (2.50 mL, 139 mmol) was stirred at room temperature for two days.The upper layer was removed by decantation and the remaining aqueouslayer was concentrated to provide5-fluoro-2,3-dimethyl-4-(piperazin-1-yl)-1H-indole-7-carboxamide HClsalt as a brown solid (166 mg, 97% yield), used without furtherpurification. Mass spectrum m/z 291 (M+H)⁺.

Intermediate 914-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide

4-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamidewas prepared following the procedures used to prepare Intermediate 2,substituting 1,1,1-trifluoro-2-butanone for 2-butanone. Mass spectrumm/z 339, 341 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 7.75 (d, J=9.7 Hz, 1H),2.70 (q, J=1.7 Hz, 3H).

Intermediate 92(RS)-5-Fluoro-3-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-2-(trifluoromethyl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 42,4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide[Intermediate 91] was converted into(RS)-5-fluoro-3-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-2-(trifluoromethyl)-1H-indole-7-carboxamideTFA salt. Mass spectrum m/z 392 (M+H)⁺.

Intermediate 93(RS)-5-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-8-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 48,8-bromo-1,2,3,4-tetrahydroisoquinoline HCl salt was converted into(RS)-5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-8-yl)-1H-indole-7-carboxamideTFA salt. Mass spectrum m/z 338 (M+H)⁺.

Intermediate 945-Fluoro-4-(indolin-6-yl)-2,3-dimethyl-1H-indole-7-carboxamide TFA Salt

Following the procedures used to prepare Intermediate 48,6-bromoindoline was converted into5-fluoro-4-(indolin-6-yl)-2,3-dimethyl-1H-indole-7-carboxamide TFA salt.Mass spectrum m/z 324 (M+H)⁺.

Intermediate 95 4-Bromo-6-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 2 fromIntermediate 2A, 4-bromo-2,6-difluorobenzoic acid was converted into4-bromo-6-fluoro-2,3-dimethyl-1H-indole-7-carboxamide. Mass spectrum m/z285, 287 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 7.08 (d, J=12.0 Hz, 1H),2.44 (d, J=0.5 Hz, 3H), 2.36 (s, 3H).

Intermediate 966-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 42,4-bromo-6-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 95]was converted into6-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideTFA salt. Mass spectrum m/z 338 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ7.45-7.38 (m, 1H), 7.37-7.31 (m, 1H), 7.29 (d, J=7.3 Hz, 1H), 6.64 (d,J=13.0 Hz, 1H), 4.48 (d, J=2.9 Hz, 2H), 3.48-3.39 (m, 2H), 2.82-2.60 (m,2H), 2.33 (s, 3H), 1.57 (d, J=0.5 Hz, 3H).

Intermediate 974-Bromo-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 2 fromIntermediate 2B, 1-cyclopropylpropan-2-one was converted into4-bromo-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide. Massspectrum m/z 312, 314 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 7.49 (d, J=9.5Hz, 1H), 2.49 (s, 3H), 1.93 (br. s., 1H), 1.04 (d, J=6.5 Hz, 2H), 0.68(d, J=4.3 Hz, 2H).

Intermediate 98(RS)-3-Cyclopropyl-5-fluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 42,4-bromo-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide[Intermediate 97] was converted into(RS)-3-cyclopropyl-5-fluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideTFA salt. Mass spectrum m/z 364 (M+H)⁺.

Intermediate 994-Bromo-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 2 fromIntermediate 2B, 1-(4-fluorophenyl)propan-2-one was converted into4-bromo-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide.Mass spectrum m/z 365, 367 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 7.51 (d,J=9.9 Hz, 1H), 7.38-7.30 (m, 2H), 7.18-7.09 (m, 2H), 2.31 (s, 3H).

Intermediate 100(RS)-5-Fluoro-3-(4-fluorophenyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 42,4-bromo-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide[Intermediate 99] was converted into(RS)-5-fluoro-3-(4-fluorophenyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideTFA salt. Mass spectrum m/z 418 (M+H)⁺.

Intermediate 1014-Bromo-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 2 fromIntermediate 2B, 1-(4-fluorophenyl)propan-1-one was converted into4-bromo-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indole-7-carboxamide.Mass spectrum m/z 365, 367 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 7.67-7.61(m, 2H), 7.56 (d, J=9.9 Hz, 1H), 7.31-7.24 (m, 2H), 2.64 (s, 3H).

Intermediate 102(RS)-5-Fluoro-2-(4-fluorophenyl)-3-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 42,4-bromo-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indole-7-carboxamide[Intermediate 101] was converted into(RS)-5-fluoro-2-(4-fluorophenyl)-3-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideTFA salt. Mass spectrum m/z 418 (M+H)⁺.

Intermediate 1035-Fluoro-2,3-dimethyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamideTFA Salt

Intermediate 103A: tert-Butyl3-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Intermediate 2] (120 mg, 0.421 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(130 mg, 0.421 mmol), K₃PO₄ (179 mg, 0.842 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (13.7 mg,0.021 mmol) in THF (2 mL) and water (0.2 mL) was purged with nitrogenand stirred at 60° C. overnight. The mixture was cooled to roomtemperature, filtered through CELITE® and concentrated. The residue wassubjected to column chromatography on silica gel, eluting withEtOAc-hexanes (gradient from 0-50%), to provide tert-butyl3-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylateas a yellow gum (135 mg, 74% yield). Mass spectrum m/z 388 (M+H)⁺.

Intermediate 103

A solution of tert-butyl3-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(69 mg, 0.178 mmol) and TFA (0.5 mL, 6.49 mmol) in DCM (1.5 mL) wasstirred at room temperature for 30 min. The mixture was concentrated toprovide5-fluoro-2,3-dimethyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamideTFA salt, as a light brown solid (70 mg, 88% yield). Mass spectrum m/z288 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 7.37 (d, J=11.1 Hz, 1H), 6.01(tt, J=3.9, 1.9 Hz, 1H), 4.03-3.80 (m, 2H), 3.57-3.39 (m, 2H), 2.72-2.62(m, 2H), 2.40-2.36 (m, 3H), 2.22 (s, 3H).

Intermediate 104(RS)-5-Fluoro-2,3-dimethyl-4-(piperidin-3-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 38,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 2]was converted into(RS)-5-fluoro-2,3-dimethyl-4-(piperidin-3-yl)-1H-indole-7-carboxamideTFA salt. Mass spectrum m/z 290 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ7.39-7.32 (m, 1H), 4.11-3.99 (m, 1H), 3.68-3.58 (m, 1H), 3.55-3.44 (m,2H), 3.16-3.03 (m, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.23-1.86 (m, 4H).

Intermediates 105 and 1065-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide(Single Enantiomers)

Intermediates 105A and 106A: tert-Butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(Single Enantiomers)

A sample of (RS)-tert-butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate[Intermediate 42A] (754 mg) was separated by chiral super-critical fluidchromatography (Column: AD-H (3×25 cm, 5 μm); mobile phase: CO₂-MeOH(85:15) at 150 mL/min; sample preparation: 37.7 mg/mL in MeOH-DCM (1:1);injection: 1 mL).

The first peak eluting from the column provided one enantiomer oftert-butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate[Intermediate 105A] as a white solid (249 mg). Mass spectrum m/z 438(M+H)⁺.

The second peak eluting from the column provided the other enantiomer oftert-butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate[Intermediate 106A] as an off-white solid (232 mg). Analytical chiralsuper-critical fluid chromatography indicated contamination by 1.5% ofthe first enantiomer. The chiral super-critical fluid chromatographicseparation was repeated to provide the second enantiomer [Intermediate106A] as a white solid (203 mg). Mass spectrum m/z 438 (M+H)⁺.

An alternative chiral super-critical fluid chromatographic separation of(RS)-tert-butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate[Intermediate 42A] (754 mg) used similar conditions but with a mobilephase consisting of CO₂-MeOH (75:25) containing 0.1% aqueous NH₄OH. Thesecond peak eluting from the column provided Intermediate 106A as awhite solid.

The absolute stereochemistries of Intermediates 105A and 106A have notbeen assigned.

Intermediate 105

A mixture of a single enantiomer of tert-butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate[Intermediate 105A](0.249 g, 0.569 mmol) and TFA (3 mL) was stirred atroom temperature for 45 min. The mixture was concentrated and theresidue was dissolved in EtOAc, washed twice with 1.5 M aqueous Na₂HPO₄,then with brine. The aqueous layers were extracted with EtOAc, and thecombined organic layers were dried and concentrated to provide a singleenantiomer of5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideas a pale yellow solid (0.192 g, 100% yield). Mass spectrum m/z 338(M+H)⁺. The absolute stereochemistry has not been assigned.

Intermediate 106

Following the procedure used to prepare Intermediate 105, a singleenantiomer of tert-butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate[Intermediate 106A] (0.203 g, 0.464 mmol) was converted into a singleenantiomer of5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamideas a pale yellow solid (0.157 g, 96% yield). Mass spectrum m/z 338(M+H)⁺. The absolute stereochemistry has not been assigned.

Intermediate 107(RS)-5-Fluoro-2,3-dimethyl-4-(2,7-diazaspiro[4.4]nonan-2-yl)-1H-indole-7-carboxamide

Following the procedures used to prepare Intermediate 26 butsubstituting with (RS)-tert-butyl7-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylatefor (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate,4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12]was converted into(RS)-5-fluoro-2,3-dimethyl-4-(2,7-diazaspiro[4.4]nonan-2-yl)-1H-indole-7-carboxamide.Mass spectrum m/z 331 (M+H)⁺.

Intermediate 1085-Fluoro-2,3-dimethyl-4-(1,4,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamideTFA Salt

Following the procedures used to prepare Intermediate 26, tert-butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylatewas converted into5-fluoro-2,3-dimethyl-4-(1,4,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamideTFA salt. Mass spectrum m/z 288 (M+H)⁺.

Intermediate 109 Ethyl4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxylate

Intermediate 109A:4-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxylicacid

A mixture of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid, HCl (5.0 g,17.51 mmol), and 1,1,1-trifluoro-2-butanone (6.62 g, 52.5 mmol) in TFA(8.0 mL) was stirred at reflux for 18 hr. The mixture was concentrated.The crude product was added to DCM and the precipitate was collected byfiltration and dried under high vacuum. Yield was4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxylicacid (3.86 g, 10.22 mmol, 58.3% yield) as white solid. ¹H NMR (400 MHz,methanol-d₄) δ 7.75 (d, J=9.3 Hz, 1H), 2.69 (q, J=1.7 Hz, 3H). LCMS:1.07 min, M+H product not ionize.

Intermediate 109

A mixture of4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxylicacid (3.86 g, 11.35 mmol) and sulfuric acid (0.605 mL, 11.35 mmol) inEtOH (80 mL) was stirred at reflux for three days. The mixture wasconcentrated. The mixture was diluted with EtOAc (65 mL) and was washedwith aqueous 1.0 M HCl (65 mL) and a solution of aqueous saturatedsodium bicarbonate (2×65 mL). The ethyl acetate layer was dried oversodium sulfate and concentrated. The crude product was subjected to ISCOflash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient).Yield was ethyl4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxylate(1.80 g, 4.65 mmol, 40.9% yield) as white solid. ¹H NMR (400 MHz,methanol-d₄) δ 7.81 (s, 1H), 4.49 (d, J=7.1 Hz, 2H), 2.76-2.65 (m, 3H),1.46 (t, J=7.2 Hz, 3H). LCMS: 1.26 min, M+H product not ionize.

Example 14-(3-Acrylamido-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide

A mixture of 4-bromo-3-methyl-1H-indole-7-carboxamide [Intermediate4](0.030 g, 0.119 mmol),N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide[Intermediate 66] (30.4 mg, 0.130 mmol), andtetrakis(triphenylphosphine)palladium (6.85 mg, 5.93 μmol) in toluene(2.22 mL) and ethanol (741 μL) was bubbled with nitrogen for about 2-5min. The mixture was treated with 2 M aqueous Na₂CO₃ (148 μL, 0.296mmol), bubbled again with nitrogen, and the vessel was sealed and heatedat 90° C. After 16 h, the mixture was cooled to room temperature andconcentrated. The residue was dissolved in DMF-MeOH, filtered, andpurified by preparative reverse-phase HPLC to provide4-(3-acrylamido-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide (21.9mg, 61% yield). Mass spectrum m/z 438 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 10.86 (s, 1H), 8.04 (br. s., 1H), 7.67 (d, J=7.4 Hz, 1H), 7.33 (br.s., 1H), 7.06 (s, 1H), 6.92 (t, J=7.7 Hz, 1H), 6.73-6.64 (m, 2H), 6.39(d, J=6.4 Hz, 1H), 4.87 (s, 2H), 1.71 (s, 3H), 1.63 (d, J=1.0 Hz, 3H).

Example 22,3-Dimethyl-4-(3-(vinylsulfonyl)phenyl)-1H-indole-7-carboxamide

A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate1](30.0 mg, 0.112 mmol),4,4,5,5-tetramethyl-2-(3-(vinylsulfonyl)phenyl)-1,3,2-dioxaborolane[Intermediate 79] (43.4 mg, 0.118 mmol), and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (3.66 mg,5.62 μmol) in THF (3 mL) was bubbled with nitrogen, treated with 2 Maqueous K₃PO₄ (0.168 mL, 0.336 mmol), bubbled again with nitrogen, andheated at 50° C. under nitrogen. After 16 h, the mixture was cooled toroom temperature and concentrated. The residue was dissolved in DMF,filtered, and purified by preparative reverse-phase HPLC to provide2,3-dimethyl-4-(3-(vinylsulfonyl)phenyl)-1H-indole-7-carboxamide (12.7mg, 30% yield). Mass spectrum m/z 355 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 10.92 (s, 1H), 8.07 (br. s., 1H), 7.93-7.89 (m, 1H), 7.80-7.72 (m,3H), 7.63 (d, J=7.4 Hz, 1H), 7.40 (br. s., 1H), 7.21 (dd, J=16.3, 9.9Hz, 1H), 6.87 (d, J=7.4 Hz, 1H), 6.38 (d, J=16.8 Hz, 1H), 6.23 (d, J=9.9Hz, 1H), 2.35 (s, 3H), 1.63 (s, 3H).

Example 35-Fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide

A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Intermediate 2] (29.0 mg, 0.102 mmol),N-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide[Intermediate 73] (32.1 mg, 0.112 mmol), and Cs₂CO₃ (83.0 mg, 0.254mmol) in 6:1 THF-water (3.39 mL) was bubbled with nitrogen, then wastreated with PdCl₂(dppf) DCM adduct (4.15 mg, 5.09 μmol). The mixturewas bubbled with nitrogen again, then heated at 50° C. under nitrogen.After 16 h, the mixture was cooled to room temperature and concentrated.The residue was dissolved in DMF, filtered, and purified by preparativereverse-phase HPLC to provide5-fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide(27 mg, 73% yield). Mass spectrum m/z 366 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 10.86 (s, 1H), 8.09 (br. s., 1H), 7.57-7.52 (m, 2H), 7.49(br. s., 1H), 7.38-7.33 (m, 2H), 7.29 (d, J=1.5 Hz, 1H), 6.22-6.06 (m,2H), 5.63-5.55 (m, 1H), 3.29 (s, 3H), 2.31 (s, 3H), 1.58 (s, 3H).

Example 42,3-Dimethyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide

A mixture of2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide[Intermediate 9] (35.0 mg, 0.0890 mmol), N-(3-bromophenyl)ethenesulfonamide [Intermediate 55] (25.7 mg, 0.0980 mmol) and Cs₂CO₃(72.6 mg, 0.223 mmol) in 4:1 THF-water (2.97 mL) was bubbled withnitrogen, then was treated with PdCl₂(dppf) DCM adduct (3.64 mg, 4.46μmol). The mixture was bubbled again with nitrogen, then was heated at50° C. under nitrogen. After 16 h, the mixture was cooled to roomtemperature and concentrated. The residue was dissolved in DMF,filtered, and purified by preparative reverse-phase HPLC to provide2,3-dimethyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (12mg, 36% yield). Mass spectrum m/z 370 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 10.82 (s, 1H), 10.08 (s, 1H), 8.02 (br. s., 1H), 7.58 (d, J=7.9 Hz,1H), 7.40-7.32 (m, 2H), 7.22-7.18 (m, 1H), 7.12 (s, 1H), 7.08 (d, J=7.4Hz, 1H), 6.84-6.73 (m, 2H), 6.11-6.01 (m, 2H), 2.33 (s, 3H), 1.66 (s,3H).

Additional Examples which were prepared by procedures described inExamples 1 through 4 or similar procedures, using the indicated startingmaterials, are shown in Table 1. (Starting materials prepared usingliterature procedures are indicated in footnotes to the Table.)

TABLE 1 Starting Mass Example Structure Materials Spectrum 5

Intermediates 1 and 66 m/z 348 (M + H)⁺ 6

Intermediates 1 and 67 m/z 362 (M + H)⁺ 7

Intermediates 5 and 66 m/z 334 (M + H)⁺ 8

Intermediates 5 and 67 m/z 348 (M + H)⁺ 9

Intermediates 4 and 67 m/z 348 (M + H)⁺ 10

Intermediates 1 and 68 m/z 376 (M + H)⁺ 11

Intermediates 5 and 68 m/z 362 (M + H)⁺ 12

Intermediates 4 and 68 m/z 362 (M + H)⁺ 13

Intermediates 1 and 70 m/z 350 (M + H)⁺ 14

Intermediates 1 and 69 m/z 362 (M + H)⁺ 15

Intermediates 1 and 64 m/z 387 (M + H)⁺ 16

Intermediates 1 and 71 m/z 405 (M + H)⁺ 17

Intermediates 1 and 61 m/z 362 (M + H)⁺ 18

Intermediates 1 and 62 m/z 402 (M + H)⁺ 19

Intermediates 4 and 63 m/z 347 (M + H)⁺ 20

Intermediates 1 and 72 m/z 362 (M + H)⁺ 21

Intermediates 1 and 80 m/z 361 (M + H)⁺ 22

Intermediates 1 and 65 m/z 334 (M + H)⁺ 23

Intermediates 1 and 75 m/z 398 (M + H)⁺ 24

Intermediates 4 and 75 m/z 384 (M + H)⁺ 25

Intermediates 1 and 76 m/z 384 (M + H)⁺ 26

Intermediates 2 and 76 m/z 402 (M + H)⁺ 27

Intermediates 3 and 76 m/z 418.420 (M + H)⁺ 28

Intermediates 4 and 76 m/z 370 (M + H)⁺ 29

Intermediates 1 and 73 m/z 348 (M + H)⁺ 30

Intermediates 4 and 73 m/z 334 (M + H)⁺ 31

Intermediates 4 and 77 m/z 370 (M + H)⁺ 32

Intermediates 1 and 74 m/z 366 (M + H)⁺ 33

Intermediates 4 and 78 m/z 356 (M + H)⁺ 34

Intermediates 1 and 77 m/z 384 (M + H)⁺ 35

Intermediates 9 and 60 m/z 374 (M + H)⁺ 36

Intermediates 9 and 58 m/z 360 (M + H)⁺ 37

Intermediates 2 and 59 m/z 378 (M + H)⁺ 38

Intermediates 9 and 52 m/z 360 (M + H)⁺ 39

Intermediates 9 and 54 m/z 396 (M + H)⁺ 40

Intermediates 9 and 56 m/z 384 (M + H)⁺ 41

Intermediates 9 and 51 m/z 348 (M + H)⁺ 42

Intermediates 9 and 57 m/z 412 (M + H)⁺ 43

Intermediates 9 and 53 m/z 335 (M + H)⁺ 44

Intermediates 10 and 53 m/z 321 (M + H)⁺ 45

Intermediates 6 and 66 m/z 320 (M + H)⁺ 46

Intermediates 6 and 72 m/z 334 (M + H)⁺ 47

Intermediates 1 and (a) m/z 424 (M + H)⁺ 48

Intermediates 1 and (b) m/z 428 (M + H)⁺ 49

Intermediates 1 and (c) m/z 423 (M + H)⁺ 50

Intermediates 1 and (d) m/z 441 (M + H)⁺ 51

Intermediates 1 and (e) m/z 440 (M + H)⁺ 52

Intermediates 6 and (d) m/z 413 (M + H)⁺ 53

Intermediates 6 and (f) m/z 413 (M + H)⁺ 54

Intermediates 6 and (g) m/z 413 (M + H)⁺ 55

Intermediates 6 and (h) m/z 429, 431 (M + H)⁺ 56

Intermediates 6 and (i) m/z 425 (M + H)⁺ 57

Intermediates 6 and (b) m/z 400 (M + H)⁺ 58

Intermediates 6 and (j) m/z 407 (M + H)⁺ 59

Intermediates 4 and (c) m/z 409 (M + H)⁺ 60

Intermediates 5 and (c) m/z 409 (M + H)⁺ 61

Intermediates 8 and (c) m/z 559 (M + H)⁺ 62

Intermediates 8 and (g) m/z 577 (M + H)⁺ 63

Intermediates 8 and (j) m/z 571 (M + H)⁺ 64

Intermediates 8 and (d) m/z 577 (M + H)⁺ 65

Intermediates 8 and (f) m/z 577 (M + H)⁺ 66

Intermediates 8 and (i) m/z 589 (M + H)⁺ 67

Intermediates 1 and 81 m/z 471 (M + H)⁺ 68

Intermediates 1 and 82 m/z 453 (M + H)⁺(a) Intermediate 50-8, (b) Intermediate 50-5, (c) Intermediate 50-24,(d) Intermediate 50-27, (e) Intermediate 50-55, (f) Intermediate 50-60,(g) Intermediate 50-48, Intermediate 50-26, (i) Intermediate 50-51, and(j) Intermediate 50-9, each from U.S. Pat. No. 8,084,620.

Example 694-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide

Example 69A:4-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indole-7-carboxamide

A solution of4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide[Intermediate 7] (0.50 g, 1.35 mmol),3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one[prepared according to the procedures of U.S. Pat. No. 8,084,620,Intermediate 50-24] (0.515 g, 1.42 mmol),tetrakis(triphenylphosphine)palladium (0.078 g, 0.068 mmol), 2.0 Maqueous Na₂CO₃ (1.69 mL, 3.38 mmol), in 5:1 toluene-ethanol (16.9 mL)was heated under a nitrogen atmosphere at 90° C. for 16 h. The mixturewas cooled to room temperature and partitioned between EtOAc andsaturated aqueous NaHCO₃. The organic phase was washed with brine, driedand concentrated. The residue was combined with that from anotheridentical reaction, and the material was purified by columnchromatography on silica gel (40 g), eluting with EtOAc-hexanes, toprovide4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indole-7-carboxamideas a glassy solid (1.40 g, 94% yield). Mass spectrum m/z 525 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.50 (1H, br. s.), 8.35 (1H, br. s.), 8.08 (1H,br. s.), 7.98-8.06 (1H, m), 7.90 (1H, d, J=7.9 Hz), 7.74 (1H, t, J=7.5Hz), 7.52-7.70 (5H, m), 7.50 (1H, d, J=7.3 Hz), 7.17 (1H, d, J=7.5 Hz),6.19-6.46 (1H, m), 5.83 (2H, d, J=7.3 Hz), 2.10 (1H, s), 1.96 (3H, s),0.86 (2H, dd, J=9.4, 6.9 Hz),−0.04-0.03 (9H, m).

Example 69

A solution of4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(40 mg, 0.076 mmol), 1.0 M tetra-n-butylammonium fluoride in THF (229μL, 0.229 mmol) and 1,2-diaminoethane (31 μL, 0.457 mmol) in DMF (762μL) was heated at 60° C. After 17 h, more tetra-n-butylammonium fluoridesolution (0.25 mL) was added and heating was continued for another day.The mixture was cooled to room temperature and treated with 1.0 Maqueous HCl and the mixture was stirred for 4 days. The mixture wasconcentrated and the residue was subjected to preparative reverse-phaseHPLC to provide4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(1.1 mg, 4% yield). Mass spectrum m/z 395 (M+H)⁺. ¹H NMR (500 MHz,MeOH-d₄) δ 8.38 (d, J=8.0 Hz, 1H), 8.24 (d, J=19.7 Hz, 1H), 7.95-7.87(m, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.68-7.62 (m,1H), 7.52 (q, J=7.8 Hz, 2H), 7.43-7.36 (m, 2H), 7.09 (d, J=15.0 Hz, 1H),6.41-6.24 (m, 1H), 1.99 (br. s., 3H).

Example 704-(3-(2-Cyano-2-(methylsulfonyl)vinyl)phenyl)-2,3-dimethyl-1H-indole-7-carboxamide

Example 70A: 4-(3-Formylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide

A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate1](50 mg, 0.187 mmol), (3-formylphenyl)boronic acid (33.7 mg, 0.225mmol), 2.0 M aqueous K₃PO₄ (0.187 mL, 0.374 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (6.1 mg,9.36 μmol) in THF (2 mL) in a sealed tube was subjected to 3evacuate-fill cycles with nitrogen. The mixture was stirred at roomtemperature for three days, then was concentrated. The residue wassubjected to column chromatography on silica gel (12 g), eluting withEtOAc-hexanes (gradient from 0-100%), to provide4-(3-formylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide as an off-whitesolid (36 mg, 66% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.17 (br. s., 1H),10.12 (s, 1H), 7.98-7.93 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 1H),7.36 (d, J=7.7 Hz, 1H), 6.96 (d, J=7.7 Hz, 1H), 2.41 (s, 3H), 1.76 (s,3H).

Example 70

A solution of 4-(3-formylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide(26 mg, 0.089 mmol) and 2-(methylsulfonyl)acetonitrile (42.4 mg, 0.356mmol) in ethanol (1 mL) was treated with1,8-diazabicyclo[5.4.0]undec-7-ene (0.054 mL, 0.356 mmol). The mixturewas stirred at room temperature for 2 h, then was combined with thereaction mixture from an identical reaction using4-(3-formylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (7.7 mg, 0.026mmol), 2-(methylsulfonyl)acetonitrile (12.6 mg, 0.105 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.016 mL, 0.105 mmol). The combinedmixtures were diluted with EtOAc, washed once with 1 M aqueous HCl andtwice with water, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (12 g), eluting with EtOAc-hexanes(gradient from 10-100%), to provide4-(3-(2-cyano-2-(methylsulfonyl)vinyl)phenyl)-2,3-dimethyl-1H-indole-7-carboxamideas a yellow solid (24 mg, 91% yield). Mass spectrum m/z 394 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 8.44 (s, 1H), 8.12-8.08 (m, 2H),8.04 (br. s., 1H), 7.73-7.70 (m, 2H), 7.64 (d, J=7.7 Hz, 1H), 7.36 (br.s., 1H), 6.86 (d, J=7.7 Hz, 1H), 2.36 (s, 3H), 1.70 (s, 3H).

Example 716-Hydroxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide

A solution of6-(4-methoxybenzyloxy)-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide[Example 61] (218 mg, 0.390 mmol) and thioanisole (369 μL, 3.12 mmol) inDCM (4.13 mL) was treated with TFA (2.07 mL) and the mixture was stirredat room temperature for 3.5 h. The mixture was concentrated andpartitioned between EtOAc and 1 M aqueous NaOH combined with saturatedaqueous NaHCO₃(pH about 9). The organic phase was washed with brine,dried and concentrated. The residue was purified by columnchromatography on silica gel (24 g), eluting with EtOAc-hexanes, toprovide6-hydroxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamideas a light yellow glassy solid (124 mg, 73% yield). Mass spectrum m/z439 (M+H)⁺.

Example 726-Ethoxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide

A mixture of6-hydroxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide [Example 71] (20 mg, 0.046 mmol),iodoethane (7 μL, 0.091 mmol), K₂CO₃ (37.8 mg, 0.274 mmol) and acetone(0.91 mL) was heated at 60° C. for 80 min. The mixture was cooled toroom temperature and subjected to preparative reverse-phase HPLC toprovide6-ethoxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(12.7 mg, 59% yield). Mass spectrum m/z 467 (M+H)⁺. ¹H NMR (500 MHz,MeOH-d₄) δ 10.45 (2s, 1H), 8.41-8.32 (m, 1H), 8.22-8.12 (2s, 1H),7.94-7.86 (m, 1H), 7.82 (t, J=7.4 Hz, 1H), 7.69-7.61 (m, 1H), 7.54-7.44(m, 2H), 7.43-7.35 (m, 1H), 6.72-6.57 (2s, 1H), 4.35-4.23 (m, 2H), 2.33(s, 3H), 1.89 (2s, 3H), 1.74-1.58 (2 s, 3H), 1.54 (t, J=6.9 Hz, 3H)(mixture of rotamers).

Additional Examples which were prepared from Example 71 by the proceduredescribed in Example 72 or similar procedures, using the indicatedalkylating agent, are shown in Table 2.

TABLE 2 Alkylating Mass Example Structure Agent Spectrum 73

iodomethane m/z 453 (M + H)⁺ 74

chloromethyl-benzene m/z 467 (M + H)⁺ 75

4-(2-chloroethyl)- HCl m/z 552 (M + H)⁺ 76

1-chloro-2-methoxyethane m/z 497 (M + H)⁺

Example 774-(3-((4,6-Dichloro-1,3,5-triazin-2-yl)amino)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide

A suspension of cyanuric chloride (0.026 mL, 0.187 mmol) and K₂CO₃ (59.0mg, 0.426 mmol) in THF (1 mL) was stirred on an ice-water bath andtreated dropwise with a solution of4-(3-amino-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide[Intermediate 41] (50.0 mg, 0.170 mmol) in THF (1 mL). The mixture wasstirred at room temperature for 2.25 h, then was filtered andconcentrated. The residue was purified by column chromatography onsilica gel (12 g), eluting with EtOAc-hexanes (gradient from 10-80%), toprovide4-(3-((4,6-dichloro-1,3,5-triazin-2-yl)amino)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamideas an off-white solid (56.8 mg, 74% yield). Mass spectrum m/z 441, 443,445 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s, 1H), 10.75 (s, 1H),8.00 (br. s., 1H), 7.61 (d, J=7.7 Hz, 1H), 7.39-7.25 (m, 3H), 7.16 (dd,J=7.2, 1.7 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 2.31 (s, 3H), 1.82 (s, 3H),1.55 (s, 3H).

Example 78(RS)-2,3-Dimethyl-4-(3-(N-methylacrylamido)piperidin-1-yl)-1H-indole-7-carboxamide

A solution of(RS)-2,3-dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide[Intermediate 35] (60.0 mg, 0.114 mmol) in 1:1 DCM-THF (2.08 mL) wascooled to 0° C. and treated with DIEA (33.8 μL, 0.194 mmol). Acryloylchloride (13.0 μL, 0.159 mmol) was added slowly and the mixture wasstirred at 0° C. After 1 h, the mixture was concentrated and the residuewas subjected to column chromatography on silica gel (4 g), eluting withEtOAc-hexanes (gradient from 50-70%), to provide(RS)-2,3-dimethyl-4-(3-(N-methylacrylamido)piperidin-1-yl)-1H-indole-7-carboxamideas a solid (23 mg, 53% yield). Mass spectrum m/z 355 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 10.17-9.93 (m, 1H), 7.24 (br. s., 1H), 6.76-6.52 (m, 2H),6.34 (d, J=16.7 Hz, 1H), 6.08-5.57 (m, 3H), 5.07-4.14 (m, 1H), 3.43 (br.s., 2H), 3.00 (d, J=6.8 Hz, 3H), 2.80-2.56 (m, 1H), 2.54-2.43 (m, 3H),2.38 (s, 3H), 1.95 (br. s., 3H), 1.83-1.60 (m, 2H).

Additional Examples which were prepared by procedure described inExample 78 or similar procedures, using the indicated starting material,are shown in Table 3.

TABLE 3 Starting Mass Example Structure Material Spectrum 79

Intermediate 17 m/z 341 (M + H)⁺ 80

Intermediate 38 m/z 326 (M + H)⁺ 81

Intermediate 14 m/z 341 (M + H)⁺ 82

Intermediate 22 m/z 327 (M + H)⁺ 83

Intermediate 15 m/z 341 (M + H)⁺ 84

Intermediate 13 m/z 341 (M + H)⁺ 85

Intermediate 23 m/z 327 (M + H)⁺ 86

Intermediate 19 m/z 327 (M + H)⁺ 87

Intermediate 27 m/z 327 (M + H)⁺ 88

Intermediate 21 m/z 345 (M + H)⁺ 89

Intermediate 16 m/z 359 (M + H)⁺ 90

Intermediate 40 m/z 312 (M + H)⁺ 91

Intermediate 25 m/z 341 (M + H)⁺ 92

Intermediate 18 m/z 359 (M + H)⁺ 93

Intermediate 39 m/z 312 (M + H)⁺ 94

Intermediate 28 m/z 341 (M + H)⁺ 95

Intermediate 42 m/z 392 (M + H)⁺ 96

Intermediate 37 m/z 359 (M + H)⁺ 97

Intermediate 43 m/z 392 (M + H)⁺ 98

Intermediate 32 m/z 371 (M + H)⁺ 99

Intermediate 46 m/z 392 (M + H)⁺ 100

Intermediate 24 m/z 345 (M + H)⁺ 101

Intermediate 47 m/z 378 (M + H)⁺ 102

Intermediate 49 m/z 394 (M + H)⁺

Example 103(RS)-2,3-Dimethyl-4-((1-propioloylpyrrolidin-3-yl)amino)-1H-indole-7-carboxamide

A solution of(RS)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide[Intermediate 19] (35 mg, 0.096 mmol), HATU (73 mg, 0.19 mmol), DIEA (51μL, 0.29 mmol) and propiolic acid (7.4 mg, 0.11 mmol) in DMF (1.4 mL)was stirred at room temperature. After 4 h, the mixture was filtered andpurified by preparative reverse-phase HPLC to provide(RS)-2,3-dimethyl-4-((1-propioloylpyrrolidin-3-yl)amino)-1H-indole-7-carboxamide(7.1 mg, 23% yield). Mass spectrum m/z 325 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 10.44 (s, 1H), 7.64 (br. s., 1H), 7.44 (d, J=8.5 Hz, 1H),6.88 (br. s., 1H), 6.15 (dd, J=18.9, 7.9 Hz, 1H), 5.20 (br. s., 1H),4.52-4.40 (m, 1H), 4.29-4.17 (m, 1H), 4.11 (br. s., 1H), 3.83-3.51 (m,3H), 2.38-2.19 (m, 7H), 2.12-1.98 (m, 1H).

Example 104(RS)-4-(1-(But-2-ynoyl)piperidin-3-yl)-3-methyl-1H-indole-7-carboxamide

A solution of (RS)-3-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide[Intermediate 39] (10.0 mg, 0.039 mmol), BOP (20.6 mg, 0.047 mmol), DIEA(68 μL, 0.39 mmol) and but-2-ynoic acid (6.5 mg, 0.078 mmol) in THF (2mL) was stirred at room temperature. After 2 h, the mixture was filteredand purified by preparative reverse-phase HPLC to provide(RS)-4-(1-(but-2-ynoyl)piperidin-3-yl)-3-methyl-1H-indole-7-carboxamide(2.8 mg, 21% yield). Mass spectrum m/z 324 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 10.84 (d, J=15.3 Hz, 1H), 7.99 (br. s., 1H), 7.63 (t, J=8.5Hz, 1H), 7.28 (br. s., 1H), 7.12 (d, J=12.8 Hz, 1H), 6.96 (dd, J=19.8,7.6 Hz, 1H), 4.50-4.39 (m, 2H), 4.36 (t, J=11.3 Hz, 2H), 3.37 (br. s.,1H), 3.32-3.25 (n, 1H), 3.24-3.15 (m, 1H), 2.81-2.70 (m, 2H), 2.05 (s,3H), 1.92 (s, 3H).

Additional Examples which were prepared by procedures described inExamples 103 and 104 or similar procedures, using the indicated startingmaterial and the appropriate carboxylic acid, are shown in Table 4.

TABLE 4 Starting Mass Example Structure Material Spectrum 105

Intermediate 35 m/z 353 (M + H)⁺ 106

Intermediate 25 m/z 339 (M + H)⁺ 107

Intermediate 17 m/z 353 (M + H)⁺ 108

Intermediate 35 m/z 367 (M + H)⁺ 109

Intermediate 13 m/z 415 (M + H)⁺ 110

Intermediate 13 m/z 411 (M + H)⁺ 111

Intermediate 13 m/z 397 (M + H)⁺ 112

Intermediate 13 m/z 367 (M + H)⁺ 113

Intermediate 13 m/z 381 (M + H)⁺ 114

Intermediate 17 m/z 339 (M + H)⁺ 115

Intermediate 13 m/z 339 (M + H)⁺ 116

Intermediate 13 m/z 353 (M + H)⁺ 117

Intermediate 14 m/z 339 (M + H)⁺ 118

Intermediate 14 m/z 353 (M + H)⁺ 119

Intermediate 23 m/z 325 (M + H)⁺ 120

Intermediate 23 m/z 339 (M + H)⁺ 121

Intermediate 19 m/z 339 (M + H)⁺ 122

Intermediate 18 m/z 371 (M + H)⁺ 124

Intermediate 26 m/z 384 (M + H)⁺ 125

Intermediate 36 m/z 385 (M + H)⁺ 126

Intermediate 16 m/z 385 (M + H)⁺ 127

Intermediate 36 m/z 399 (M + H)⁺ 128

Intermediate 16 m/z 399 (M + H)⁺ 129

Intermediate 42 m/z 404 (M + H)⁺ 130

Intermediate 33 m/z 399 (M + H)⁺ 131

Intermediate 44 m/z 392 (M + H)⁺ 132

Intermediate 45 m/z 378 (M + H)⁺ 133

Intermediate 45 m/z 390 (M + H)⁺ 134

Intermediate 44 m/z 404 (M + H)⁺ 135

Intermediate 24 m/z 357 (M + H)⁺ 136

Intermediate 16 m/z 397 (M + H)⁺ 137

Intermediate 47 m/z 390 (M + H)⁺

Example 138(RS)-2,3-Dimethyl-4-(3-(N-methylvinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide

A solution of(RS)-2,3-dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide[Intermediate 35] (60 mg, 0.11 mmol) in 1:1 DCM-THF (2.08 mL) was cooledto −20° C. and treated with DIEA (40 μL, 0.23 mmol). A solution of2-chloroethanesulfonyl chloride (21 μL, 0.21 mmol) in DCM (296 μL) wasadded slowly and the mixture was stirred at 0° C. After 1 h the mixturewas concentrated. The residue was subjected to column chromatography onsilica gel (4 g), eluting with EtOAc-hexanes (gradient from 25-50%), toprovide (RS)-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide as a solid (20 mg, 44% yield).Mass spectrum m/z 391 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (s, 1H),7.81 (br. s., 1H), 7.48 (d, J=8.1 Hz, 1H), 7.12 (br. s., 1H), 6.84 (dd,J=16.4, 10.0 Hz, 1H), 6.59 (d, J=7.9 Hz, 1H), 6.14-5.99 (m, 2H),4.00-3.84 (m, 1H), 3.21 (d, J=10.8 Hz, 2H), 2.74 (s, 4H), 2.55 (br. s.,1H), 2.33 (d, J=12.3 Hz, 6H), 1.88-1.58 (m, 4H).

Additional Examples which were prepared by procedure described inExample 138 or similar procedures, using the indicated startingmaterials, are shown in Table 5.

TABLE 5 Starting Mass Example Structure Material Spectrum 139

Intermediate 15 m/z 377 (M + H)⁺ 140

Intermediate 22 m/z 363 (M + H)⁺ 141

Intermediate 13 m/z 377 (M + H)⁺ 142

Intermediate 23 m/z 363 (M + H)⁺ 143

Intermediate 14 m/z 377 (M + H)⁺ 144

Intermediate 19 m/z 363 (M + H)⁺ 145

Intermediate 34 m/z 363 (M + H)⁺ 146

Intermediate 16 m/z 395 (M + H)⁺  34*

Intermediate 41 m/z 384 (M + H)⁺ *Alternative preparation of Example 34.

Example 147(S)-4-((1-Cyanopyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

A mixture of(S)-5-fluoro-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide[Intermediate 21] (0.041 g, 0.127 mmol) and Cs₂CO₃ (0.166 g, 0.508 mmol)in DMF (1.5 mL) was cooled to 0° C. and treated with 5M cyanogen bromidein acetonitrile (0.028 mL, 0.140 mmol). The mixture was stirred at 0° C.for 60 min., then at room temperature overnight. The mixture was dilutedwith water and extracted with EtOAc. The organic layer was washed twicewith 10% aqueous LiCl, then with brine. The combined aqueous layers wereextracted with EtOAc, and the combined organic layers were dried andconcentrated. The residue was subjected to column chromatography onsilica gel, eluting with EtOAc-hexanes (gradient from 50-75%), to give(S)-4-((1-cyanopyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamideas a yellow solid (0.007 g, 17% yield). Mass spectrum m/z 316 (M+H)⁺.

Additional Examples which were prepared by procedures described inExample 147 or similar procedures, using the indicated startingmaterial, are shown in Table 6.

TABLE 6 Starting Mass Example Structure Material Spectrum 148

Intermediate 38 m/z 297 (M + H)⁺ 149

Intermediate 40 m/z 283 (M + H)⁺ 150

Intermediate 16 m/z 330 (M + H)⁺ 151

Intermediate 18 m/z 330 (M + H)⁺ 152

Intermediate 42 m/z 363 (M + H)⁺

Examples 153 and 1544-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(Single Enantiomers)

A sample of(RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 95] (42 mg) was separated by chiral super-critical fluidchromatography (Column: IC (3×25 cm, 5 μm); mobile phase: CO₂-MeOH(55:45) at 150 mL/min; sample preparation: 5.83 mg/mL in MeOH-DCM (4:1);injection: 2 mL).

The first peak eluting from the column provided one enantiomer of4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 153] as a pale yellow solid (18 mg). Mass spectrum m/z 392(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.08 (br. s., 1H),7.53 (d, J=10.7 Hz, 1H), 7.48 (br. s., 1H), 7.33-7.28 (m, 2H), 7.15-7.10(m, 1H), 6.93 (dd, J=16.7, 10.5 Hz, 0.4H), 6.80 (dd, J=16.6, 10.5 Hz,0.6H), 6.14 (d, J=16.6 Hz, 1H), 5.73 (d, J=10.7 Hz, 0.4H), 5.67 (dd,J=10.5, 1.9 Hz, 0.6H), 4.87 (s, 1H), 4.77 (d, J=3.8 Hz, 1H), 3.78-3.62(m, 1H), 3.60-3.52 (m, 1H), 2.44-2.31 (m, 2H), 2.31-2.24 (m, 3H), and1.43-1.38 (m, 3H).

The second peak eluting from the column provided the other enantiomer of4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 154] (18 mg). Mass spectrum m/z 392 (M+H)⁺. NMR: same asExample 153.

The absolute stereochemistries of Examples 153 and 154 have not beenassigned.

Alternative Preparation of4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(Single Enantiomer) [Example 153]

Following the procedure used to prepare Example 78, a single enantiomerof5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide[Intermediate 105] (20 mg, 0.059 mmol) was converted into a singleenantiomer of4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamidein 91% yield.

Alternative Preparation of4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(Single Enantiomer) [Example 154]

Following the procedure used to prepare Example 78, a single enantiomerof5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide[Intermediate 106] (2.85 g, 8.45 mmol) was converted into a singleenantiomer of4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamidein 78% yield.

Examples 155 and 1564-(4-Acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(Single Enantiomers)

A sample of(RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 102] (25 mg) was separated by chiral super-critical fluidchromatography (Column: CHIRALPAK@ IC, 3×25 cm, 5 μm; mobile phase:CO₂-MeOH 55:45 at 150 mL/min, 35° C.; sample preparation: dissolved in1:1 MeOH-DCM; injection 1.0 mL).

The first peak eluting from the column provided one enantiomer of4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 155] as an off-white solid (10.4 mg). Mass spectrum m/z 394(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.04 (br. s., 1H),7.60-7.38 (m, 3H), 7.08-6.95 (m, 2H), 6.82 (dd, J=16.8, 10.4 Hz, 1H),6.30 (dd, J=16.8, 2.1 Hz, 1H), 5.91-5.80 (m, 1H), 4.17 (t, J=4.6 Hz,2H), 4.08-3.95 (m, 1H), 3.83 (dt, J=13.6, 4.9 Hz, 1H), 2.29 (s, 3H),1.57 (s, 3H).

The second peak eluting from the column provided the other enantiomer of4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 156] (11 mg). Mass spectrum m/z 394 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 10.73 (s, 1H), 8.04 (br. s., 1H), 7.57-7.35 (m, 3H),7.05-6.95 (m, 2H), 6.82 (dd, J=16.7, 10.3 Hz, 1H), 6.30 (dd, J=16.9, 2.0Hz, 1H), 5.90-5.80 (m, 1H), 4.17 (t, J=4.6 Hz, 2H), 4.01 (dt, J=13.7,4.4 Hz, 1H), 3.83 (dt, J=13.5, 4.9 Hz, 1H), 2.29 (s, 3H), 1.57 (s, 3H).

The absolute stereochemistries of Examples 155 and 156 have not beenassigned.

Examples 157 and 1584-(2-Cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(Single Enantiomers)

A sample of(RS)-4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 152] (25 mg) was separated by chiral super-critical fluidchromatography (Column: AD-H (3×25 cm, 5 μm); mobile phase: CO₂-MeOH(65:35) at 150 mL/min; 100 bar, 40° C.; sample preparation: 4.39 mg/mLin MeOH; injection: 1 mL).

The first peak eluting from the column provided one enantiomer of4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 157] as an off-white solid (11 mg). Mass spectrum m/z 363(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.84 (s, 1H), 8.08 (br. s., 1H),7.54 (d, J=10.7 Hz, 1H), 7.49 (br. s., 1H), 7.34-7.29 (m, 1H), 7.23 (d,J=7.0 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H), 4.52 (s, 2H), 3.38 (t, J=6.3 Hz,2H), 2.39 (t, J=5.9 Hz, 2H), 2.29 (s, 3H), and 1.43 (s, 3H).

The second peak eluting from the column provided the other enantiomer of4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 158] (18 mg). Mass spectrum m/z 363 (M+H)⁺. NMR: same asExample 157.

The absolute stereochemistries of Examples 157 and 158 have not beenassigned.

Examples 159 and 160cis-4-(1-Acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(Single Enantiomers)

Example 159A:(RS)-cis-4-(1-Acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Example 78,5-fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide[Intermediate 29] was converted into(RS)-cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamideas a yellow solid in 57% yield. Mass spectrum m/z 385 (M+H)⁺. ¹H NMR(500 MHz, MeOH-d₄) complex due to a mixture of rotamers. At 60° C.: 67.36 (d, J=13.6 Hz, 1H), 6.80 (br. s., 1H), 6.18 (d, J=16.5 Hz, 1H),5.75 (br. s., 1H), 2.43 (s, 3H), 2.36 (s, 3H). Methylene and methineprotons complex but consistent with expected structure.

Examples 159 and 160

A sample of(RS)-cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(30 mg) was separated by chiral super-critical fluid chromatography(Column: OJ (3×25 cm, 5 μm); mobile phase: CO₂-MeOH (85:15) at 170mL/min; 100 bar, 40° C.; sample preparation: 2.5 mg/mL in MeOH-DCM).

The first peak eluting from the column provided one enantiomer ofcis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 159] as an off-white solid (10.7 mg). The second peak elutingfrom the column provided the other enantiomer ofcis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 160] as an off-white solid (11.8 mg). Mass spectra and NMRspectra for both enantiomers were the same as those observed for theracemic mixture.

The absolute stereochemistries of Examples 159 and 160 have not beenassigned.

Examples 161 to 164cis-4-(3-Acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(Single Diastereomers)

Example 161A:cis-4-(3-Acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(Mixture of Four Diastereomers)

Following the procedures used to prepare Example 78,(RS-cis)-5-fluoro-2,3-dimethyl-4-(1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-1H-indole-7-carboxamideTFA salt [Intermediate 48] was converted intocis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,a mixture of four diastereomers, as a gum in 86% yield. Mass spectrumm/z 404 (M+H)⁺.

Examples 161 Through 164

A sample ofcis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,mixture of four diastereomers (29 mg) was separated by chiralsuper-critical fluid chromatography (Column: AS-H, 5×25 cm, 5 μm; mobilephase: CO₂-MeOH (72:28) at 280 mL/min, 100 bar; sample preparation: 2.9mg/mL in MeOH).

The first peak eluting from the column was subjected to columnchromatography on silica gel, eluting with 10% MeOH/EtOAc-hexanes(gradient from 0-100%), to provide one diastereomer ofcis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 161] (1.09 mg).

The second peak eluting from the column provided a second diastereomerofcis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 162] (5.46 mg).

The third peak eluting from the column provided a third diastereomer ofcis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 163] (5.72 mg).

The fourth peak eluting from the column provided a fourth diastereomerofcis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 164] (5.37 mg).

The absolute stereochemistries of Examples 161 through 164 have not beenassigned. The mass spectra for all four were the same as that of Example161A.

Additional Examples which were prepared by procedures described forExamples 159 through 164 or similar procedures, using the indicatedstarting material, are shown in Table 7.

TABLE 7 Starting Mass Example Structure Material Spectrum 165 (peak 1)

Intermediate 30 m/z 371 (M + H)⁺ 166 (peak 2)

Intermediate 30 m/z 371 (M + H)⁺ 167 (peak 1)

Intermediate 31 m/z 371 (M + H)⁺ 168 (peak 2)

Intermediate 31 m/z 371 (M + H)⁺ 169 (peak 1)

Intermediate 50 m/z 410 (M + H)⁺ 170 (peak 2)

Intermediate 50 m/z 410 (M + H)⁺ 171 (peak 3)

Intermediate 50 m/z 410 (M + H)⁺ 172 (peak 4)

Intermediate 50 m/z 410 (M + H)⁺

Examples 173 and 174cis-4-(1-(But-2-ynoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(Single Enantiomers)

Example 173A:(RS)-cis-4-(1-(But-2-ynoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Example 103 but substitutingbut-2-ynoic acid for propiolic acid,5-fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide[Intermediate 29] was converted into(RS)-cis-4-(1-(but-2-ynoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamideas a yellow gum in 75% yield. Mass spectrum m/z 397 (M+H)⁺. ¹H NMR (500MHz, MeOH-d₄) complex due to mixture of rotamers.

Examples 173 and 174

A sample of(RS)-cis-4-(1-(but-2-ynoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(32 mg) was separated by chiral super-critical fluid chromatography(Column: OJ-H (3×25 cm, 5 μm); mobile phase: CO₂-MeOH (85:15) at 150mL/min; 40° C.; sample preparation: 3.2 mg/mL in MeOH).

The first peak eluting from the column provided one enantiomer ofcis-4-(1-(but-2-ynoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 173] as a white solid (9.2 mg). The second peak eluting fromthe column provided the other enantiomer ofcis-4-(1-(but-2-ynoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 174] as an off-white solid (9.8 mg). Mass spectra and NMRspectra for both enantiomers were the same as those observed for theracemic mixture.

The absolute stereochemistries of Examples 173 and 174 have not beenassigned.

Additional Examples which were prepared by procedures described forExamples 173 and 174 or similar procedures, using the indicated startingmaterial, are shown in Table 8.

TABLE 8 Starting Mass Example Structure Material Spectrum 175 (peak 1)

Intermediate 30 m/z 383 (M + H)⁺ 176 (peak 2)

Intermediate 30 m/z 383 (M + H)⁺ 177 (peak 1)

Intermediate 31 m/z 383 (M + H)⁺ 178 (peak 2)

Intermediate 31 m/z 383 (M + H)⁺

Examples 179 and 180cis-4-(1-Cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(Single Enantiomers)

Example 179A:(RS)-cis-4-(1-Cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedures used to prepare Example 147,(RS-cis)-5-fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide[Intermediate 29] was converted into(RS)-cis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamideas a brown gum in 34% yield. Mass spectrum m/z 356 (M+H)⁺.

Examples 179 and 180

A sample of(RS)-cis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(12 mg) was separated by chiral super-critical fluid chromatography(Column: CHIRALPAK® AS-H 5×25 cm, 5 μm; mobile phase CO₂-MeOH 75:25 at280 mL/min, 30° C.; sample preparation: dissolved in MeOH; injection: 1mL).

The first peak eluting from the column provided one enantiomer ofcis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 179] as a white solid (4.2 mg). Mass spectrum m/z 356 (M+H)⁺.The second peak eluting from the column provided the other enantiomer ofcis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Example 180] as a white solid (4.5 mg). Mass spectrum m/z 356 (M+H)⁺.

The absolute stereochemistries of Examples 179 and 180 have not beenassigned.

Example 1815-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide,TFA Salt

Example 181A:4-Bromo-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile

A solution of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile[Intermediate 12] (1.50 g, 5.62 mmol) in THF (15 mL) at −78° C. wastreated with 1.0 M lithium bis(trimethylsilyl)amide in THF (6.74 mL,6.74 mmol) and the mixture was stirred at −78° C. for 15 min.(2-(Chloromethoxy)ethyl)trimethylsilane (0.983 g, 5.90 mmol) was addedand the mixture was stirred at room temperature for 2 h. The mixture wasdiluted with EtOAc (45 mL), washed sequentially with saturated aqueousNaHCO₃ (2×45 mL) and 1.0 M aqueous HCl (45 mL), dried and concentrated.The residue was subjected to column chromatography on silica gel,eluting with EtOAc-hexanes (gradient from 0-30%), to provide4-bromo-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile as a white solid (1.92 g, 82% yield).¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, J=8.4 Hz, 1H), 5.77 (s, 2H),3.68-3.60 (m, 2H), 2.52 (d, J=0.5 Hz, 3H), 2.43 (s, 3H), 0.95 (dd,J=8.7, 7.7 Hz, 2H),−0.01 (s, 9H).

Example 181B:4-((6-Chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile

A suspension of4-bromo-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile (238 mg, 0.599 mmol) in THF (5.0 mL)was treated with 0.5 M (2-chloro-5-pyridyl)methylzinc chloride in THF(1.32 mL, 0.659 mmol) and tetrakis(triphenylphosphine)palladium (25.6mg, 0.022 mmol) and the mixture was stirred at reflux for 18 h. Themixture was diluted with EtOAc (15 mL), washed twice with saturatedaqueous NaHCO₃, dried and concentrated. The residue was subjected tocolumn chromatography on silica gel, eluting with EtOAc-hexanes(gradient from 0-60%), to provide4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrileas a colorless gum (201 mg, 72% yield). Mass spectrum m/z 444, 446(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=2.1 Hz, 1H), 7.31-7.25 (m,2H), 7.23-7.18 (m, 1H), 5.78 (s, 2H), 4.44 (s, 2H), 3.73-3.59 (m, 2H),2.41 (s, 3H), 2.26 (d, J=0.4 Hz, 3H), 0.97 (dd, J=8.6, 7.6 Hz, 2H),−0.01(s, 9H).

Example 181C:4-((6-Chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

A solution of4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile(200 mg, 0.450 mmol) in THF (2.0 mL) was treated with a solution of 1.0M tetra-n-butylammonium fluoride in THF (4.50 mL, 4.50 mmol), and themixture was heated at reflux for 18 h. The cooled mixture was dilutedwith EtOAc and washed twice with saturated aqueous NaHCO₃, dried andconcentrated. The residue was subjected to column chromatography onsilica gel, eluting with EtOAc-hexanes (gradient from 0-30%), to provide4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrileas a white solid (90 mg, 61% yield). Mass spectrum m/z 314, 316 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 8.37 (br. s., 1H), 8.25 (d, J=2.3 Hz, 1H),7.33 (ddd, J=8.2, 2.5, 0.6 Hz, 1H), 7.25-7.16 (m, 2H), 4.43 (s, 2H),2.41 (s, 3H), 2.26 (d, J=0.4 Hz, 3H).

Example 181D:5-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carbonitrile

A mixture of4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile(28 mg, 0.089 mmol), tri-n-butyl(vinyl)stannane (85 mg, 0.268 mmol),LiCl (11.4 mg, 0.268 mmol) and tetrakis(triphenylphosphine)palladium(10.3 mg, 8.92 μmol) in DMF (1.0 mL) under a nitrogen atmosphere washeated at 90° C. for 18 h. The cooled mixture was diluted with EtOAc,washed twice with saturated aqueous NaHCO₃, dried and concentrated. Theresidue was subjected to column chromatography on silica gel, elutingwith EtOAc-hexanes (gradient from 0-30%) to provide5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carbonitrileas a white solid (22 mg, 77% yield). Mass spectrum m/z 306 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.44 (d, J=2.0 Hz, 1H), 8.38 (br. s., 1H), 7.32(dd, J=8.1, 1.7 Hz, 1H), 7.25-7.22 (m, 1H), 7.20 (d, J=9.5 Hz, 1H), 6.79(dd, J=17.5, 10.9 Hz, 1H), 6.15 (dd, J=17.5, 1.2 Hz, 1H), 5.44 (dd,J=10.8, 1.3 Hz, 1H), 4.45 (s, 2H), 2.40 (s, 3H), 2.26 (d, J=0.2 Hz, 3H).

Example 181

5-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carbonitrile(22 mg, 0.072 mmol) was cooled in an ice-bath and treated withchlorotrimethylsilane (921 μL, 7.20 mmol), then with water (65 μl, 3.60mmol) and the mixture was stirred at room temperature for 18 h. Thesupernatant was removed and the residue was dissolved in DMF andpurified by preparative HPLC, eluting with MeOH-water containing 0.1%TFA (gradient from 20-100%). The appropriate effluent fractions werelyophilized from 1:1 water-acetonitrile (10 mL) to provide5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide,TFA salt, as an off-white powder (15.8 mg, 48% yield). Mass spectrum m/z324 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.43 (d, J=1.3 Hz, 1H),8.25-8.16 (m, 1H), 8.14-8.07 (m, 1H), 7.43 (d, J=11.0 Hz, 1H), 6.95 (dd,J=17.6, 11.2 Hz, 1H), 6.48 (d, J=17.6 Hz, 1H), 6.01 (d, J=11.2 Hz, 1H),4.67 (s, 2H), 2.38 (s, 3H), 2.26 (s, 3H).

Example 1825-Fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carboxamide,TFA Salt

Example 182A:5-Fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carbonitrile

Following the procedure used to prepare Example 181D but substitutingtri-n-butyl(prop-1-yn-1-yl)stannane for tri-n-butyl(vinyl)stannane,4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile[Example 181C] was converted into5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carbonitrilein 44% yield. Mass spectrum m/z 318 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.46-8.37 (m, 2H), 7.25 (d, J=1.3 Hz, 2H), 7.20 (d, J=9.4 Hz, 1H), 4.44(d, J=1.6 Hz, 2H), 2.40 (s, 3H), 2.24 (d, J=0.4 Hz, 3H), 2.07 (s, 3H).

Example 182

Following the procedure used to convert Example 181D into Example 181,5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carbonitrilewas converted into5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carboxamide,TFA salt, in 48% yield. Mass spectrum m/z 336 (M+H)⁺. ¹H NMR (400 MHz,MeOH-d₄) δ 8.41 (d, J=1.6 Hz, 1H), 8.00 (dd, J=8.3, 2.1 Hz, 1H), 7.76(d, J=8.3 Hz, 1H), 7.43 (d, J=11.0 Hz, 1H), 4.64 (s, 2H), 2.39 (s, 3H),2.25 (s, 3H), 2.19 (s, 3H).

Examples 183 and 1845-Fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carboxamide,TFA Salt (Single Enantiomers)

Example 183A:(RS)-4-(1-(6-Chloropyridin-3-yl)ethyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile

A solution of4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile[Example 181B] (91 mg, 0.205 mmol) in THF (5.0 mL) at −78° C. wastreated with 1.0 M potassium bis(trimethylsilyl) amide in THF (0.615 mL,0.615 mmol), then with iodomethane (0.038 mL, 0.615 mmol). The mixturewas stirred at −78° C. for 1 h, then was warmed to room temperature,diluted with EtOAc, washed with saturated aqueous NaHCO₃, dried andconcentrated. The residue was subjected to column chromatography onsilica gel, eluting with EtOAc-hexanes (gradient from 0-30%), to provide(RS)-4-(1-(6-chloropyridin-3-yl)ethyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrileas a colorless gum (90 mg, 91% yield). Mass spectrum m/z 458, 460(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J=2.2 Hz, 1H), 7.53 (ddd,J=8.3, 1.7, 0.9 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.14 (d, J=11.1 Hz,1H), 5.79 (s, 2H), 5.15 (q, J=6.9 Hz, 1H), 3.75-3.62 (m, 2H), 2.46 (s,3H), 2.45 (s, 3H), 1.82 (dd, J=7.2, 1.5 Hz, 3H), 0.97 (dd, J=8.7, 7.8Hz, 2H), 0.00 (s, 9H).

Example 183B:(RS)-5-Fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carbonitrile

Following the procedures used to convert Example 181B into Example 181D,(RS)-4-(1-(6-chloropyridin-3-yl)ethyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile was converted into(RS)-5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carbonitrilein 65% yield (two steps). Mass spectrum m/z 320 (M+H)⁺.

Examples 183 and 184

A sample of(RS)-4-(1-(6-chloropyridin-3-yl)ethyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile(45 mg) was separated by chiral super-critical fluid chromatography(Column: AD-H, 3×25 cm, 5 μm; mobile phase: CO₂-MeOH (70:30) at 150mL/min; 35° C., 100 bar; sample preparation: 4.5 mg/mL; injection: 2.0mL).

Concentration of the first peak eluting from the column provided aresidue (14 mg) which was converted into one enantiomer of5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carboxamide,TFA salt, as a white powder [Example 183] (11.6 mg) by following theprocedure used to convert Example 181D to Example 181. Mass spectrum m/z338 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.58 (s, 1H), 8.41 (dd, J=8.6,2.0 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.31 (d, J=12.7 Hz, 1H), 7.00 (dd,J=17.6, 11.2 Hz, 1H), 6.52 (d, J=17.6 Hz, 1H), 6.06 (d, J=11.2 Hz, 1H),5.37 (q, J=6.8 Hz, 1H), 2.48 (s, 3H), 2.45 (s, 3H), 1.92 (dd, J=7.2, 1.0Hz, 3H).

Concentration of the second peak eluting from the column provided aresidue (14 mg) which likewise was converted into the other enantiomerof5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carboxamide,TFA salt, as a white powder [Example 184] (10.6 mg) by following theprocedure used to convert Example 181D to Example 181. Mass spectrum andNMR: same as those of Example 183.

Example 1855-Fluoro-2,3-dimethyl-4-((2-vinylpyridin-4-yl)methyl)-1H-indole-7-carboxamide

Example 185A:4-((6-Chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile

Chlorotrimethylsilane (2.7 μL, 0.021 mmol) and 1,2-dibromoethane (3.2μL, 0.043 mmol) were added to a suspension of zinc (84 mg, 1.28 mmol) inTHF (1.5 mL) and the mixture was stirred at 65° C. for 20 min. Themixture was cooled to 0° C., treated dropwise with a solution of2-chloro-4-(chloromethyl)pyridine (139 mg, 0.856 mmol) in THF (0.5 mL)and stirred for 20 min. A solution of4-bromo-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile[Example 181A] (170 mg, 0.428 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (27.9mg, 0.043 mmol) was added and the mixture was slowly warmed to roomtemperature and stirred for 1 h. The mixture was heated at 60° C.overnight, then was cooled to room temperature and filtered through apad of CELITE®. The filtrate was diluted with DCM, washed sequentiallywith saturated aqueous NaHCO₃ and water, and dried and concentrated. Theresidue was subjected to column chromatography on silica gel, elutingwith EtOAc-hexanes (gradient from 0-50%), to provide4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrileas a yellow glassy solid (168.5 mg, 75% yield). Mass spectrum m/z 444,446 (M+H)⁺.

Example 185B:4-((2-Chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

A mixture of4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile(130 mg, 0.293 mmol) and tetra-n-butylammonium fluoride (1 M in THF)(2.93 mL, 2.93 mmol) in THF (1 mL) was stirred at 70° C. for 3 h. Themixture was diluted with EtOAc, washed twice with saturated aqueousNaHCO₃, dried and concentrated. The residue was subjected to columnchromatography on silica gel, eluting with EtOAc-hexanes (gradient from0-100%) to provide4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrileas a yellow solid (38 mg, 29% yield). Mass spectrum m/z 314, 316 (M+H)⁺.

Example 185C:4-((2-Chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,TFA Salt

A mixture of4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile(45 mg, 0.143 mmol), chlorotrimethylsilane (2.5 mL, 19.6 mmol) and water(1 mL, 55.5 mmol) was stirred at room temperature overnight. The toplayer was removed by decantation and the lower aqueous layer wasconcentrated. The residue was purified using preparative reverse-phaseHPLC to provide4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,TFA salt, as a white solid (18.7 mg, 29% yield). Mass spectrum m/z 332,334 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.21 (d, J=5.1 Hz, 1H), 7.41 (d,J=11.0 Hz, 1H), 7.17-7.07 (m, 2H), 4.51 (s, 2H), 2.37 (s, 3H), 2.19 (s,3H).

Example 185

Following the procedure used to convert Example 181C to Example 181D,4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide,TFA salt, was converted into5-fluoro-2,3-dimethyl-4-((2-vinylpyridin-4-yl)methyl)-1H-indole-7-carboxamidein 74% yield. Mass spectrum m/z 324 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ8.31 (d, J=5.3 Hz, 1H), 7.41 (d, J=10.9 Hz, 1H), 7.27 (s, 1H), 6.98 (dd,J=5.3, 1.1 Hz, 1H), 6.74 (dd, J=17.6, 11.0 Hz, 1H), 6.05 (dd, J=17.6,1.1 Hz, 1H), 5.45 (dd, J=11.0, 1.0 Hz, 1H), 4.51 (s, 2H), 2.36 (s, 3H),2.19 (d, J=0.2 Hz, 3H).

Additional Examples which were prepared by procedures described above,using the starting material(s) and procedures indicated, are shown inTable 9.

TABLE 9 Starting Mass Example Structure Materials Procedures Spectrum186 (racemic)

Intermediate 84 (a) m/z 408 (M + H)⁺ 187 single enantiomer (peak 1)

Example 186 (b) m/z 408 (M + H)⁺ 188 single enantiomer (peak 2)

Example 186 (b) m/z 408 (M + H)⁺ 189 (racemic)

Intermediate 85 (a) m/z 410 (M + H)⁺ 190 single enantiomer (peak 1)

Example 189 (b) m/z 410 (M + H)⁺ 191 single enantiomer (peak 2)

Example 189 (b) m/z 410 (M + H)⁺ 192

Intermediate 86 (a) m/z 392 (M + H)⁺ 193 racemic

Intermediate 87 (a) m/z 378 (M + H)⁺ 194 racemic

Intermediate 88 (a) m/z 410 (M + H)⁺ 195 single enantiomer (peak 1)

Example 194 (b) m/z 410 (M + H)⁺ 196 single enantiomer (peak 2)

Example 194 (b) m/z 410 (M + H)⁺ 197 racemic

Intermediate 92 (a) m/z 446 (M + H)⁺ 198 single enantiomer (peak 1)

Example 197 (b) m/z 446 (M + H)⁺ 199 single enantiomer (peak 2)

Example 197 (b) m/z 446 (M + H)⁺ 200

Intermediate 89 (c) m/z 411 (M + H)⁺ 201

Intermediate 90 (c) m/z 357 (M + H)⁺ 202

Intermediate 90 (a) m/z 345 (M + H)⁺ 203

Intermediate 86 (c) m/z 404 (M + H)⁺ 204 racemic

Intermediate 93 (a) m/z 392 (M + H)⁺ 205 single enantiomer (peak 1)

Example 204 (b) m/z 392 (M + H)⁺ 206 single enantiomer (peak 2)

Example 204 (b) m/z 392 (M + H)⁺ 207

Intermediate 94 (a) m/z 378 (M + H)⁺ 208

Intermediate 96 (a) m/z 392 (M + H)⁺ 209 racemic

Intermediate 98 (a) m/z 418 (M + H)⁺ 210 single enantiomer (peak 1)

Example 209 (b) m/z 418 (M + H)⁺ 211 single enantiomer (peak 2)

Example 209 (b) m/z 418 (M + H)⁺ 212 racemic

Intermediate 100 (a) m/z 472 (M + H)⁺ 213 single enantiomer (peak 1)

Example 212 (b) m/z 472 (M + H)⁺ 214 single enantiomer (peak 2)

Example 212 (b) m/z 472 (M + H)⁺ 215 racemic

Intermediate 102 (a) m/z 472 (M + H)⁺ 216

Intermediate 103 (a) m/z 342 (M + H)⁺ 217 racemic

Intermediate 104 (a) m/z 344 (M + H)⁺ 218 single enantiomer (peak 1)

Example 217 (b) m/z 344 (M + H)⁺ 219 single enantiomer (peak 2)

Example 217 (b) m/z 344 (M + H)⁺ 220 racemic

Intermediate 104 (c) m/z 356 (M + H)⁺ (a) Prepared following theprocedure used to prepare Example 78 or similar procedures. (b) Preparedby super-critical fluid chromatography of the racemic compound. Absoluteconfiguration was not assigned. (c) Prepared following the procedureused to prepare Example 103 or similar procedures.

Example 2215-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carboxamide

Example 221A:5-Fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile

Following the procedure used to prepare Intermediate 9,4-bromo-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile[Example 181A] was converted into5-fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrileas a white solid in 45% yield. Mass spectrum m/z 445 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.15 (d, J=8.6 Hz, 1H), 5.76 (s, 2H), 3.58 (dd, J=8.6, 7.6Hz, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 1.45 (s, 12H), 0.95-0.88 (m,2H),−0.03 (s, 9H).

Example 221B:4-((6-Chloropyridin-2-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile

A mixture of 2-(bromomethyl)-6-chloropyridine hydrochloride (19.1 mg,0.079 mmol),5-fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile(35 mg, 0.079 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladiumdichloride (2.6 mg, 3.94 μmol) and K₃PO₄ (67 mg, 0.315 mmol) in THF (300μL) and water (150 μL) was stirred at room temperature under nitrogen.After 18 h, the mixture was diluted with EtOAc (2 mL), dried andconcentrated. The residue was subjected to column chromatography onsilica gel, eluting with EtOAc-hexanes (gradient from 0-30%) to provide4-((6-chloropyridin-2-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrileas a colorless gum (29 mg, 79% yield). Mass spectrum m/z 444, 446(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (t, J=7.8 Hz, 1H), 7.29-7.24 (m,1H), 7.16 (dd, J=7.9, 0.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 5.76 (s, 2H),4.62 (d, J=1.3 Hz, 2H), 3.69-3.62 (m, 2H), 2.38 (s, 3H), 2.25 (s, 3H),1.00-0.91 (m, 2H),−0.02 (s, 9H).

Example 221C:5-Fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carbonitrile

Following the procedure used to convert Example 181C to Example 181D,4-((6-chloropyridin-2-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrilewas converted into 5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carbonitrileas a colorless gum in 74% yield. Mass spectrum m/z 436 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.49 (t, J=7.8 Hz, 1H), 7.31-7.24 (m, 1H), 7.17 (d,J=7.6 Hz, 1H), 6.82 (dd, J=17.5, 10.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H),6.19 (dd, J=17.5, 1.5 Hz, 1H), 5.78 (s, 2H), 5.47 (dd, J=10.8, 1.3 Hz,1H), 4.65 (d, J=1.7 Hz, 2H), 3.71-3.61 (m, 2H), 2.40 (s, 3H), 2.33 (s,3H), 1.03-0.92 (m, 2H),−0.01 (s, 9H).

Example 221D:5-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carbonitrile

Following the procedure used to convert Example 181B to Example 181C,5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carbonitrilewas converted into5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carbonitrileas a white solid in 49% yield. Mass spectrum m/z 306 (M+H)⁺.

Example 221

Following the procedure used to convert Example 181D to Example 181,5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carbonitrilewas converted into5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carboxamideas a white powder in 30% yield. Mass spectrum m/z 324 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 9.94 (br. s., 1H), 7.47 (t, J=7.8 Hz, 1H), 7.17 (d,J=7.7 Hz, 1H), 7.10 (d, J=10.4 Hz, 1H), 6.85 (dd, J=17.5, 10.9 Hz, 1H),6.78 (d, J=7.8 Hz, 1H), 6.22 (dd, J=17.5, 1.3 Hz, 1H), 5.49 (dd, J=10.8,1.3 Hz, 1H), 4.67 (d, J=1.6 Hz, 2H), 2.37 (s, 3H), 2.30 (s, 3H).

Example 2225-Fluoro-4-((5-fluoro-6-vinylpyridin-3-yl)methyl)-2,3-dimethyl-1H-indole-7-carboxamide

Example 222A:4-((6-Chloro-5-fluoropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Following the procedure used to convert Example 221A into Example 221B,5-fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide[Intermediate 83] and 5-(bromomethyl)-2-chloro-3-fluoropyridine[prepared according to the procedure of U.S. Pat. No. 8,188,292, ExampleVII step 1] were converted into4-((6-chloro-5-fluoropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamideas a colorless gum in 60% yield. Mass spectrum m/z 350, 352 (M+H)⁺.

Example 222

Following the procedure used to convert Example 181C to Example 181D,4-((6-chloro-5-fluoropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamidewas converted into5-fluoro-4-((5-fluoro-6-vinylpyridin-3-yl)methyl)-2,3-dimethyl-1H-indole-7-carboxamideas a white powder in 22% yield. Mass spectrum m/z 342 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.43 (d, J=11.0 Hz, 1H), 7.20 (d,J=11.2 Hz, 1H), 6.94 (ddd, J=17.5, 11.2, 1.1 Hz, 1H), 6.29 (dd, J=17.5,1.7 Hz, 1H), 5.57 (dd, J=11.2, 1.5 Hz, 1H), 4.54 (s, 2H), 2.39 (s, 3H),2.26 (s, 3H).

Example 223(S)-4-(3-(But-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Intermediate 223A:4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

To a homogeneous solution of4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (3.43 g, 12.0mmol) in tetrahydrofuran (25 mL) at room temperature was addedphosphoryl trichloride (2.24 mL, 24.1 mmol) dropwise via syringe. Thereaction mixture was stirred for 3.5 days. The heterogeneous reactionmixture was concentrated under reduced pressure. The residue was dilutedwith ethyl acetate, and the resulting solid was collected by vacuumfiltration, washed with ethyl acetate, and dried to give4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (2.56 g, 9.58mmol, 80% yield) as a yellow solid. The product had a UPLC ret.time=1.31 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min.gradient); Solvent A=10% AcCN, 90% H₂O, 0.1% TFA; Solvent B=90% AcCN,10% H₂O, 0.1% TFA. LC/MS M+1=268.2.

Intermediate 223B: (S)-Benzyl(1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate

A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile(2.37 g, 8.86 mmol), (S)-benzyl piperidin-3-ylcarbamate (2.49 g, 10.6mmol), and (S)-benzyl piperidin-3-ylcarbamate (2.49 g, 10.6 mmol) indioxane (50 mL) was degassed with vacuum and nitrogen (3×). BINAP (0.276g, 0.443 mmol) was added followed by Pd₂(dba)₃ (0.405 g, 0.443 mmol),and the mixture was degassed (3×). The reaction mixture was immersed inan oil bath at 103° C. and stirred for ˜36 h. After cooling to roomtemperature, the reaction mixture was diluted with ethyl acetate, washedwith water, and washed with brine. The organic layer was collected, andthe aqueous layers were sequentially extracted with ethyl acetate (2×).The combined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashsilica gel chromatography using a mixture of ethyl acetate in hexane togive (S)-benzyl(1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate(1.08 g, 2.57 mmol, 29% yield) as a pale yellow solid. The product had aUPLC ret. time=1.40 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5min. gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90%MeCN, 10% H₂O, 0.1% TFA. LC/MS M+1=421.5.

Intermediate 223C:(S)-4-(3-Aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

A mixture of (S)-benzyl (1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate (1.00 g, 2.38 mmol) and 90% aqueous sulfuricacid (14.1 ml, 238 mmol) was immersed in an oil bath at 60° C. andstirred for 60 min. To the reaction mixture, cooled to 0° C., was addedsodium hydroxide (10M) (47.6 ml, 476 mmol) dropwise with stirring. A fewadditional drops of the sodium hydroxide solution was added until the pHwas ˜7. The mixture was extracted with ethyl acetate, resulting in asuspension. The mixture was filtered under reduced pressure, and thesolid was washed well with water. Drying under reduced pressure provided(S)-4-(3-aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(0.724 g, 2.37 mmol, 99% yield) as a tan solid. The product had a UPLCret. time=0.767 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min.gradient); Solvent A=10% AcCN, 90% H₂O, 0.1% TFA; Solvent B=90% AcCN,10% H₂O, 0.1% TFA. LC/MS M+1=305.2.

Example 223

A mixture of(S)-4-(3-aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(0.171 g, 0.562 mmol), but-2-ynoic acid (0.094 g, 1.124 mmol), HATU(0.470 g, 1.24 mmol), and Hunig's Base (0.343 mL, 1.97 mmol) inN,N-dimethylformamide (5.0 mL) was stirred at room temperature for 60min. HPLC analysis indicated that the reaction was complete. The mixturewas diluted with ethyl acetate, washed with water, washed with 10%aqueous lithium chloride (2×), washed with brine and dried overanhydrous sodium sulfate. Concentration under reduced pressure followedby purification by flash silica gel chromatography using a mixture ofethyl acetate in hexane afforded(S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(0.130 g, 0.351 mmol, 63% yield) as a white solid. The product had aUPLC ret. time=1.00 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5min. gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90%MeCN, 10% H₂O, 0.1% TFA. LC/MS M+1=371.4. ¹H NMR (500 MHz, DMSO-d₆) δ10.61 (s, 1H), 8.46 (d, J=6.3 Hz, 1H), 7.90 (br. s., 1H), 7.42-7.37 (m,1H), 7.31 (br. s., 1H), 3.96-3.84 (m, 1H), 3.13 (d, J=7.6 Hz, 1H),3.05-2.93 (m, 2H), 2.80 (br. s., 1H), 2.36 (s, 3H), 2.33-2.29 (m, 3H),1.93 (s, 3H), 1.87 (d, J=8.5 Hz, 1H), 1.71 (br. s., 2H), and 1.32 (br.s., 1H).

Alternative Preparation of Example 223 Intermediate 223D:4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

To a 100 mL 3-neck flask was added4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (40.4 g, 142 mmol)and dichloromethane (810 mL). To the resulting heterogeneous mixture wasadded pyridine (50 g, 2.5 eq) and phosphoryl trichloride (19.8 ml, 213mmol) dropwise at room temperature over 2 minutes. The reaction mixturewas stirred for 20 min. The solvent was removed under reduced pressure,water was added to the residue, and the mixture was stirred for 30 min.The precipitate was collected by filtration and dried to give4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (35 g, 131 mmol,92% yield) as a tan solid.

Intermediate 223E:(S)-tert-Butyl(1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate

A mixture of (S)-tert-butyl piperidin-3-ylcarbamate (33.9 g, 169 mmol),4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (41.13 g, 154mmol), cesium carbonate (100 g, 308 mmol), and BINAP (9.59 g, 15.40mmol) in 1,4-dioxane (1380 ml) was degassed by bubbling nitrogen for 5min. To the mixture was added Pd₂(dba)₃ (7.05 g, 7.70 mmol), and thereaction mixture was stirred at reflux for 24 h. The reaction mixturewas diluted with ethyl acetate (750 mL) and washed with water (1000 mL),washed with brine (100 mL), and dried over anhydrous sodium sulfate.Concentration under reduced pressure afforded the crude product as abrown solid, which was passed through a pad (5″) of silica gel withethyl acetate (900 mL) to remove any inorganics. The reddish crudeproduct was then purified by recrystallization from acetonitrile to givetwo crops of (S)-tert-butyl(1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate(53 g, 108 mmol, 86% yield).

Intermediate 223F:(S)-4-(3-Aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

To a 100 mL 3-neck flask was added sulfuric acid (90 g). The solutionwas heated to 60° C. (S)-tert-Butyl(1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate (21 g, 54.3 mmol) was added portionwise over aperiod of 1.5 h. The reaction mixture was stirred at 60° C. for 1 h. Thereaction mixture was added to ice and warmed to room temperature withstirring. The water phase was extracted with dichloromethane (3×) toremove organic impurities. The water phase was adjusted to pH 8, and thesolution was extracted with ethyl acetate (2×). The combined organiclayers were washed with brine (500 mL), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give(S)-4-(3-aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(13.6 g, 44.7 mmol, 82% yield) as a yellow solid.

Example 223

To a 500 mL 3-neck flask were added(S)-4-(3-aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(33.2 g, 109 mmol) in N,N-dimethylformamide (364 mL), but-2-ynoic acid(11.9 g, 142 mmol), HATU (62.2 g, 164 mmol), and Hunig's Base (38.1 ml,218 mmol) (temperature rose to 35° C.). The resulting solution wasstirred at room temperature for 1.5 h. The mixture was diluted withethyl acetate (250 mL) and washed with water (500 mL). The organic phasewas separated, and the aqueous layer was extracted with ethyl acetate(2×250 mL) (layer separation was helped by adding small amount of NaCl).The combined organic extracts were washed with water (with small amountof NaCl) (4×500 mL), washed with brine (500 mL), and dried overanhydrous sodium sulfate. Concentration under reduced pressure affordedthe crude product, which was purified by recrystallization from ethylacetate to give(S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(31 g, 83 mmol, 76% yield) as a white solid.

Example 2244-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iodo-2,3-dimethyl-1H-indole-7-carboxamide

Intermediates 224A-1 and 224A-2: Mixture of tert-butyl5-((2R,3R)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylateand tert-butyl5-((2R,3S)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of tert-butyl5-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(650 mg, 1.549 mmol) in dichloromethane (20 mL) was added sodiumcyanoborohydride (487 mg, 7.75 mmol) and acetic acid (1.77 mL, 31.0mmol). The resulted mixture was stirred at room temperature for 12 h.Purification by reverse-phase preparative HPLC afforded tert-butyl5-((2R,3R)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(350 mg, 53.6% yield) and tert-butyl5-((2R,3S)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(250 mg, 38.3% yield) as white solids.

The cis product had a UPLC ret. time=1.17 min.—Column: PHENOMENEX®Kinetex C18 2.1×50 mm (1.5 min. gradient); Solvent A=10% MeCN, 90% H₂O,0.1% TFA; Solvent B=90% MeCN, 10% H₂O, 0.1% TFA. MS (E+) m/z: 546.2(M+H). ¹H NMR (400 MHz, chloroform-d) δ 7.27-7.18 (m, 3H), 7.15-7.02 (m,2H), 4.73 (dd, J=16.7, 5.8 Hz, 2H), 4.58 (d, J=16.8 Hz, 1H), 3.95-3.84(m, 2H), 3.69-3.58 (m, 1H), 3.46-3.22 (m, 2H), 3.02-2.92 (m, 1H),2.90-2.78 (m, 1H), 2.67 (dd, J=6.8, 5.3 Hz, 1H), 2.62-2.40 (m, 2H),2.01-1.89 (m, 2H), 1.40-1.24 (m, 5H), 0.86 (d, J=6.8 Hz, 2H), and 0.76(d, J=7.0 Hz, 2H).

The trans product had a UPLC ret. time=1.23 min.—Column: PHENOMENEX®Kinetex C18 2.1×50 mm (1.5 min. gradient); Solvent A=10% MeCN, 90% H₂O,0.1% TFA; Solvent B=90% MeCN, 10% H₂O, 0.1% TFA. MS (E+) m/z: 546.2(M+H). ¹H NMR (400 MHz, chloroform-d) δ 7.27-7.17 (m, 3H), 7.14-7.02 (m,2H), 6.57 (dd, J=8.0, 2.3 Hz, 2H), 4.73 (dd, J=16.7, 6.2 Hz, 2H), 4.58(d, J=16.9 Hz, 2H), 3.72-3.60 (m, 2H), 3.02-2.93 (m, 1H), 2.68 (d, J=1.5Hz, 1H), 2.62-2.42 (m, 2H), 1.40-1.34 (m, 3H), 1.32 (d, J=6.4 Hz, 2H),0.86 (d, J=6.8 Hz, 2H), and 0.76 (d, J=7.0 Hz, 2H).

Intermediate 224B: tert-Butyl5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a suspension of tert-butyl5-((2R,3R)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(350 mg, 0.830 mmol) in tetrahydrofuran (5 mL) was addedN-iodosuccinimide (280 mg, 1.25 mmol) and a drop of pyridine (0.201 mL,2.49 mmol). The resulting mixture was stirred at 70° C. for 1 h.Purification by reverse-phase preparative HPLC afforded tert-butyl5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(150 mg, 0.275 mmol, 33% yield) as a white solid. The product had a UPLCret. time=1.38 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min.gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90% MeCN,10% H₂O, 0.1% TFA. MS (E+) m/z: 546.2 (M+H). ¹H NMR (400 MHz,chloroform-d) δ 7.82 (s, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.25 (d, J=7.3 Hz,1H), 7.02 (d, J=7.3 Hz, 1H), 4.69 (s, 2H), 3.57 (br. s., 2H), 2.49-2.23(m, 5H), 1.50 (br. s., 9H), and 1.43-1.35 (m, 3H).

Intermediate 224B: Alternative Preparation

To a suspension of tert-butyl5-((2R,3S)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(300 mg, 0.712 mmol) in tetrahydrofuran (5 mL) was addedN-iodosuccinimide (240 mg, 1.07 mmol) and a drop of pyridine (0.20 mL,2.49 mmol). The resulting mixture was stirred at room temperature for 1h, and then DDQ (188 mg, 0.830 mmol) was added, kept stirring foranother 1 h. Purification by reverse-phase preparative HPLC affordedtert-butyl5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(100 mg, 0.183 mmol, 26% yield) as a white solid. The product had a UPLCret. time=1.38 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min.gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90% MeCN,10% H₂O, 0.1% TFA. MS (E+) m/z: 546.2 (M+H).

Intermediates 224C-1 and 224C-2: tert-Butyl5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(Atropisomers 1 and 2)

tert-Butyl5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(70 mg, dissolved in 12 mL 9:1 MeOH/CH₂Cl₂) was resolved into itscorresponding enantiomers using chiral supercritical fluidchromatography (SFC) with the following conditions. Column,CHIRALPAK®-IC, 3 cm×25 cm, 5 μM; mobile phase, 45% MeOH/CO₂; flow rate,120 mL/min; detection, UV (220 nM). Column temperature: 35° C.,pressure: 100 bars BPR.

Example 224-Atropisomer 1

A solution of tert-butyl5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(Atropisomer 1; 10 mg, 0.018 mmol) in trifluoroacetic acid (0.5 mL, 6.49mmol) was stirred at room temperature for 10 min. The trifluoroaceticacid was removed under reduced pressure. The resulting mixture wasdissolved in tetrahydrofuran (1 mL), and to the solution was added DIEA(9.61 μl, 0.055 mmol) and acryloyl chloride (1.99 mg, 0.022 mmol). Thereaction mixture was stirred at room temperature for another 10 min.Purification by reverse-phase preparative HPLC afforded4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iodo-2,3-dimethyl-1H-indole-7-carboxamide(Atropisomer 1; 6 mg, 66% yield) as a white solid. The product had aUPLC ret. time=1.08 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5min. gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90%MeCN, 10% H₂O, 0.1% TFA. MS (E+) m/z: 500.2 (M+H). ¹H NMR (400 MHz,methanol-d₄) δ 8.07 (s, 1H), 7.43-7.28 (m, 2H), 7.07-6.99 (m, 1H), 6.78(dd, J=16.8, 10.6 Hz, 1H), 6.33-6.21 (m, 1H), 5.87-5.68 (m, 1H),3.86-3.68 (m, 3H), 2.57-2.27 (m, 5H), 1.96-1.83 (m, 1H), and 1.43-1.31(m, 3H).

Example 224-Atropisomer 2

The title compound was prepared in a manner similar to that of thepreparation of the Example 1. The product had a UPLC ret. time=1.08min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min. gradient);Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90% MeCN, 10% H₂O, 0.1%TFA. MS (E+) m/z: 500.2 (M+H). ¹H NMR (400 MHz, methanol-d₄) δ 8.07 (s,1H), 7.43-7.27 (m, 2H), 7.07-6.98 (m, 1H), 6.78 (dd, J=16.8, 10.6 Hz,1H), 6.26 (d, J=16.8 Hz, 1H), 5.89-5.69 (m, 1H), 4.95-4.89 (m, 1H), 3.78(q, J=6.2 Hz, 2H), 2.56-2.27 (m, 6H), and 1.45-1.33 (m, 3H).

Example 2254-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

Intermediate 225A:4-Bromo-7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine

A 0.5M tetrahydrofuran solution of (E)-but-2-en-2-ylmagnesium bromide(295 ml, 147 mmol) was added at −70° C. to a stirred solution of5-bromo-2-chloro-3-nitropyridine (10 g, 42.1 mmol) in tetrahydrofuran(80 mL). The reaction mixture was allowed to come to −35° C. over 30min. and then quenched with a saturated aqueous solution of ammoniumchloride, extracted with ethyl acetate, and dried over magnesiumsulfate. The crude product was purified ISCO flash chromatography(silica gel/hexane-EtOAc 100:0 to 0:100 gradient) followed bytrituration with hexanes-ether to afford4-bromo-7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (1 g, 3.85 mmol,9.2% yield) as a pink solid. LC/MS M+1=261.1 and 263.1.

Intermediate 225B:5-(7-Chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of 4-bromo-7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine(0.500 g, 1.927 mmol), tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.831 g, 2.31 mmol), tripotassium phosphate (2 M in water) (2.89 mL,5.78 mmol), and tetrahydrofuran (10 mL) was degassed with vacuum andnitrogen (3×). 1,1′-Bis(di-tert-butylphosphino)ferrocene palladiumdichloride (0.063 g, 0.096 mmol) was added, and the reaction mixture wasdegassed (2×). The mixture was stirred at room temperature overnight.The reaction mixture was diluted with ethyl acetate, washed with water,washed with brine, and dried over anhydrous sodium sulfate.Concentration under reduced pressure followed by purification purifiedby ISCO flash chromatography (40 g column; gradient: 0%-100% ethylacetate in hexane) afforded tert-butyl5-(7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.681 g, 1.65 mmol, 86% yield) as a yellow solid. The product had aUPLC ret. time=1.17 min. Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5min. gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90%MeCN, 10% H₂O, 0.1% TFA. LC/MS M+1=412.5 and 414.5.

Intermediate 225C: tert-Butyl5-(7-cyano-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of tert-butyl5-(7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.300 g, 0.728 mmol), zinc cyanide (0.051 g, 0.437 mmol), zinc (5.71mg, 0.087 mmol), and 1,1′-bis(diphenylphosphine)ferrocene (DPPF) (0.048g, 0.087 mmol) in N,N-dimethylacetamide (4 mL) was degassed well withvacuum and nitrogen (3×). To the mixture was addedtris(dibenzylideneacetone) dipalladium(0) (0.040 g, 0.044 mmol), withdegassing, and the reaction mixture was immersed in an oil bath at 130°C. for 6.5 h. The reaction was then cooled and stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate,washed with 10% aqueous lithium chloride (2×), and washed with brine.The organic layer was collected, and the aqueous layers weresequentially extracted with ethyl acetate (2×). The combined organiclayers were dried over anhydrous sodium sulfate. Concentration underreduced pressure followed by purification by ISCO flash chromatography(24 g column; gradient: 0%-100% ethyl acetate in hexane) affordedtert-butyl5-(7-cyano-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.153 g, 0.380 mmol, 52% yield) as a yellow film. The product had aUPLC with a ret. time=1.29 min. Column: PHENOMENEX® Kinetex C18 2.1×50mm (1.5 min. gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; SolventB=90% MeCN, 10% H₂O, 0.1% TFA. LC/MS M+1=403.5.

Intermediate 225D:2,3-Dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

A mixture of tert-butyl5-(7-cyano-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.152 g, 0.378 mmol) and 90% aqueous sulfuric acid (4.47 ml, 76 mmol)was immersed in an oil bath at 60° C. and stirred for 60 min. To thereaction mixture, cooled to 0° C., was added an aqueous solution ofsodium hydroxide (10M) (15.1 mL, 151 mmol) dropwise with stirring. A fewadditional drops of the sodium hydroxide solution were added until thepH was ˜9. The resulting suspension was stirred overnight. Theprecipitate was collected by vacuum filtration and washed well withwater and dried to give2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(0.097 g, 0.288 mmol, 76% yield) as a tan solid. The product had a UPLCret. time=0.698 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min.gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90% MeCN,10% H₂O, 0.1% TFA. LC/MS M+1=324.2.

The filtrate was extracted with dichloromethane (3×), and the organiclayer was dried over anhydrous sodium sulfate to give2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(0.024 g, 0.074 mmol, 20% yield) as a pale yellow solid.

Example 225

To a mixture of2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(0.097 g, 0.303 mmol) and Hunig's Base (0.212 mL, 1.21 mmol) intetrahydrofuran (2.0 mL) at room temperature was added acryloyl chloride(0.025 mL, 0.303 mmol). The reaction mixture was stirred for 20 min. Thereaction mixture was diluted with dichloromethane, washed with water,and dried over anhydrous sodium sulfate. Concentration under reducedpressure followed by purification by ISCO flash chromatography (12 gcolumn; gradient: 0%-5% methanol in dichloromethane) provided4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(0.039 g, 0.103 mmol, 34% yield) as a pale yellow solid. The product hada UPLC ret. time=0.807 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm(1.5 min. gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; SolventB=90% MeCN, 10% H₂O, 0.1% TFA. LC/MS M+1=375.1. ¹H NMR (500 MHz,DMSO-d₆) δ 11.27 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.82 (s, 1H), 7.60 (d,J=1.8 Hz, 1H), 7.32 (d, J=7.2 Hz, 2H), 7.18-7.11 (m, 1H), 6.96-6.73 (m,1H), 6.13 (d, J=16.6 Hz, 1H), 5.76-5.63 (m, 1H), 4.93-4.81 (m, 1H), 4.77(s, 1H), 3.76-3.55 (m, 2H), 2.45-2.38 (m, 1H), 2.37 (s, 3H), 2.33 (br.s., 1H), and 1.56-1.49 (m, 3H).

Example 2264-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(Mixture of Atropisomers)

Intermediate 226A:4-Bromo-7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine

To a stirred solution of 3-bromo-6-chloro-2-methyl-5-nitropyridine (2.00g, 7.95 mmol) in tetrahydrofuran (16 mL) at −78° C. was added(E)-but-2-en-2-ylmagnesium bromide (0.5M in THF) (55.7 mL, 27.8 mmol).The reaction mixture was allowed to warm to ˜−35° C. over 30 min. andwas then quenched with a saturated aqueous solution of ammoniumchloride. The mixture was diluted with ethyl acetate, washed with asaturated aqueous solution of ammonium chloride, washed with brine, anddried over anhydrous sodium sulfate. The organic layer was collected,and the aqueous layers were sequentially washed extracted with ethylacetate (2×). The combined organic layers were dried over anhydroussodium sulfate, and the resulting residue was purified by ISCO flashsilica gel chromatography (24 g column; gradient: 0%-100 ethyl acetatein hexane) to give4-bromo-7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine (0.402 g,1.47 mmol, 19% yield) as a yellow solid. The product had a UPLC ret.time=1.14 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min.gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90% MeCN,10% H₂O, 0.1% TFA. LC/MS M+1=273.2 and 275.2.

Intermediate 226B: tert-Butyl5-(7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of 4-bromo-7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine(0.400 g, 1.46 mmol), tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.630 g, 1.76 mmol), tripotassium phosphate (2M in water) (2.19 mL,4.39 mmol), and tetrahydrofuran (8 mL) was degassed with vacuum andnitrogen (3×). 1,1′-Bis(di-tert-butylphosphino)ferrocene palladiumdichloride (0.048 g, 0.073 mmol) was added, and the reaction mixture wasdegassed (2×). The reaction mixture was stirred at room temperatureovernight. The mixture was diluted with ethyl acetate, washed withwater, washed with brine, and dried over anhydrous sodium sulfate.Concentration under reduced pressure followed by purification purifiedby ISCO flash chromatography (40 g column; gradient: 0%-100% ethylacetate in hexane) afforded tert-butyl5-(7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.331 g, 0.777 mmol, 53% yield) as a yellow solid. The product had aUPLC ret. time=1.09 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5min. gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90%MeCN, 10% H₂O, 0.1% TFA. LC/MS M+1=426.5 and 428.4.

Intermediate 226C: tert-Butyl5-(7-cyano-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of tert-butyl5-(7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.331 g, 0.777 mmol), zinc cyanide (0.055 g, 0.466 mmol), zinc (6.10mg, 0.093 mmol), and 1,1′-bis(diphenylphosphine) ferrocene (DPPF) (0.052g, 0.093 mmol) in N,N-dimethylacetamide (4 mL) was degassed well withvacuum and nitrogen (3×). To the mixture was addedtris(dibenzylideneacetone)dipalladium(0) (0.043 g, 0.047 mmol), withdegassing, and the reaction mixture was immersed in an oil bath at 130°C. for 6 h. The mixture was then stirred overnight at room temperature.The reaction mixture was diluted with ethyl acetate, washed with 10%aqueous lithium chloride (2×), and washed with brine. The organic layerwas collected, and the aqueous layers were sequentially extracted withethyl acetate (2×). The combined organic layers were dried overanhydrous sodium sulfate. Concentration under reduced pressure followedby purification by ISCO flash chromatography (24 g column; gradient:0%-100% ethyl acetate in hexane) afforded tert-butyl5-(7-cyano-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.164 g, 0.394 mmol, 51% yield) as a yellow film. The product had aUPLC ret. time=1.21 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5min. gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90%MeCN, 10% H₂O, 0.1% TFA. LC/MS M+1=417.5.

Intermediate 226D:2,3,5-Trimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

A mixture of tert-butyl5-(7-cyano-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.164 g, 0.394 mmol) and 90% aqueous sulfuric acid (4.66 ml, 79 mmol)was immersed in an oil bath at 60° C. and stirred for 60 min. UPLC andLCMS indicated that the reaction was complete. To the reaction mixturecooled to 0° C. was added sodium hydroxide (10M) (15.8 ml, 157 mmol)dropwise with stirring. A few additional drops of the sodium hydroxidesolution were added until the pH was ˜9. The resulting solid wascollected by vacuum filtration and washed with water, washed with ethylacetate, and dried to give2,3,5-trimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(0.043 g, 0.129 mmol, 33% yield as a yellow solid. The ethyl acetatelayer was collected and washed with brine. The organic layer wascollected, and the aqueous layers were sequentially extracted with ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated to give2,3,5-trimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(0.026 g, 0.078 mmol, 20% yield) as a pale yellow solid. The product hada UPLC ret. time=0.708 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm(1.5 min. gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; SolventB=90% MeCN, 10% H₂O, 0.1% TFA. LC/MS M+1=335.4.

Example 226

To a mixture of2,3,5-trimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(0.043 g, 0.129 mmol) and Hunig's Base (0.090 mL, 0.514 mmol) intetrahydrofuran (1 mL) at room temperature was added acryloyl chloride(0.686 mL, 8.45 mmol). The reaction mixture was stirred for 30 min. Thereaction mixture was diluted with ethyl acetate, washed with water,washed with brine, and dried over anhydrous sodium sulfate. The productmixture was concentrated under reduced pressure, and the residue waspurified by ISCO flash chromatography (4 g column; gradient: 0%-5%methanol in dichloromethane) to give4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(0.025 g, 0.064 mmol, 50% yield) as a pale yellow solid. The product hada UPLC ret. time=0.798 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm(1.5 min. gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; SolventB=90% MeCN, 10% H₂O, 0.1% TFA. LC/MS M+1=389.6.

Examples 227 and 2284-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(Mixture of Atropisomers)

A sample of4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(Intermediate 2E, mixture of two atropisomers) was separated by chiralsuper-critical fluid chromatography using the following preparativeconditions to give two isolated and stable atropisomers.

Preparative Chromatographic Conditions: Instrument: Thar350; Column:Cellulose-4 (3×25 cm; 5 μm); BPR pressure: 100 bars; Temperature: 35°C.; Flow rate: 150 mL/min; mobile phase: CO₂/MeOH (55/45); detectorwavelength: 220 nm; injection: 2.5 mL; sample preparation: 21 mg/7 mLMeOH, 3 mg/mL.

Atropisomer 1 (Peak 1): The product was >99% pure by UPLC with a ret.time=0.793 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min.gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90% MeCN,10% H₂O, 0.1% TFA. LC/MS M+1=389.4. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05(s, 1H), 8.03 (d, J=2.8 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.32 (d, J=5.7Hz, 2H), 7.09-7.05 (m, 1H), 6.93 (dd, J=16.3, 10.4 Hz, 0.4H), 6.78 (dd,J=16.8, 10.4 Hz, 0.6H), 6.13 (d, J=16.8 Hz, 1H), 5.76-5.63 (m, 1H), 4.88(br. s., 1H), 4.77 (s, 1H), 3.74-3.57 (m, 2H), 2.31 (s, 3H), 3.32 (s,3H), 2.29-2.21 (m, 2H), and 2.19 (s, 2H).

Atropisomer 2 (Peak 2): The product had a UPLC ret. time=0.803min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min. gradient);Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90% MeCN, 10% H₂O, 0.1%TFA. LC/MS M+1=389.3. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.03(d, J=2.6 Hz, 1H), 7.58 (d, J=2.7 Hz, 1H), 7.36-7.27 (m, 2H), 7.10-7.04(m, 1H), 6.93 (dd, J=16.6, 10.6 Hz, 0.4H), 6.78 (dd, J=16.6, 10.5 Hz,0.6H), 6.13 (d, J=16.6 Hz, 1H), 5.76-5.63 (m, 1H), 4.88 (br. s., 1H),4.77 (s, 1H), 3.74-3.58 (m, 2H), 3.30 (s, 3H), 2.31 (s, 3H), 2.28-2.22(m, 2H), and 2.19 (s, 3H).

Example 2294-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-cyano-2,3-dimethyl-1H-indole-7-carboxamide

Intermediate 229A: tert-Butyl5-(7-carbamoyl-5-cyano-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of tert-butyl5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(25 mg, 0.046 mmol) and zinc cyanide (5.38 mg, 0.046 mmol) inN,N-dimethylformamide (1 mL) was degassed well with vacuum and nitrogen(3×). To the mixture was added Pd(Ph₃P)₄ (5.30 mg, 4.58 μmol), theyellow heterogeneous solution was degassed (3×), immersed in an oil bathat 100° C., and stirred for 12 h. During the reaction, the mixturechanged from a yellow heterogeneous solution to a dark homogeneoussolution. Purification by reverse-phase preparative HPLC afforded5-(7-carbamoyl-5-cyano-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(15 mg, 0.034 mmol, 74% yield) as a white solid. The product had a UPLCret. time=1.24 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min.gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90% MeCN,10% H₂O, 0.1% TFA. MS (E+) m/z: 445.3 (M+H).

Example 229

A solution of tert-butyl5-(7-carbamoyl-5-cyano-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(10 mg, 0.022 mmol) in trifluoroacetic acid (0.5 mL, 6.49 mmol) wasstirred at room temperature for 10 min., and then concentrated undervacuum to remove TFA. Further dried on vacuum pump. The resulted mixturewas dissolved in tetrahydrofuran (1 mL), and to the solution was addedDIEA (0.012 mL, 0.067 mmol), BOP (11.9 mg, 0.027 mmol), and but-2-ynoicacid (2.27 mg, 0.027 mmol). The reaction mixture was stirred at roomtemperature for another 10 min. Purification by reverse-phasepreparative HPLC afforded4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-cyano-2,3-dimethyl-1H-indole-7-carboxamide(6.4 mg, 71% yield) as a white solid. The product had a UPLC ret.time=0.980 min.—Column: PHENOMENEX® Kinetex C18 2.1×50 mm (1.5 min.gradient); Solvent A=10% MeCN, 90% H₂O, 0.1% TFA; Solvent B=90% MeCN,10% H₂O, 0.1% TFA. MS (E+) m/z: 399.3 (M+H). ¹H NMR (400 MHz,methanol-d₄) δ 7.82 (s, 1H), 7.43-7.27 (m, 2H), 7.09-7.01 (m, 1H), 6.78(dd, J=16.8, 10.6 Hz, 1H), 6.28 (m, 1H), 5.89-5.69 (m, 1H), 4.95-4.89(m, 1H), 3.78 (q, J=6.2 Hz, 2H), 2.55-2.27 (m, 6H), and 1.44-1.32 (m,3H).

Example 2304-((1-Acryloylpiperidin-4-yl)methyl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide

Intermediate 230A: tert-Butyl4-((7-carbamoyl-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indol-4-yl)methylene)piperidine-1-carboxylate

A mixture of4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(100 mg, 0.295 mmol), tert-butyl 4-methylenepiperidine-1-carboxylate(116 mg, 0.590 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (19.22 mg, 0.029 mmol), N,N-dicyclohexylmethylamine(0.094 mL, 0.442 mmol) and tetrabutylammonium chloride (8.20 mg, 0.029mmol) in degassed DMA (2.0 mL) under nitrogen was stirred in a seal vialat 80° C. for 18 hr. The mixture was diluted with EtOAc (15 mL) and waswashed with a solution of aqueous saturated sodium bicarbonate (2×15mL). The ethyl acetate layer was dried over sodium sulfate andconcentrated. The crude product was purified by prep-HPLC (PHENOMENEX®,Luna 5μ 30×250 mm, flow rate=30 ml/min., gradient=20% A to 100% B in 30min., A=H₂O/MeOH/TFA (90:10:0.1), B═H₂O/MeOH/TFA (10:90:0.1)). Yieldtert-butyl4-((7-carbamoyl-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indol-4-yl)methylene)piperidine-1-carboxylate(108 mg, 0.225 mmol, 76% yield) as white solid. ¹H NMR (400 MHz,methanol-d₄) δ 7.75-7.65 (m, 1H), 6.89-6.72 (m, 1H), 3.86-3.70 (m, 1H),3.51-3.39 (m, 1H), 3.25-3.03 (m, 2H), 2.61 (d, J=1.6 Hz, 4H), 2.49-2.39(m, 1H), 1.96-1.81 (m, 1H), 1.76-1.60 (m, 1H), 1.51 (s, 9H). LCMS: 1.21min., M+H 456.

Example 230

To a solution of tert-butyl4-((7-carbamoyl-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indol-4-yl)methylene)piperidine-1-carboxylate(15 mg, 0.033 mmol) and triethyl silane (0.263 mL, 1.647 mmol) in DCM(1.0 mL) was added TFA (0.254 mL, 3.29 mmol), the mixture was stirred atroom temperature for 30 min. The mixture was concentrated to give crude5-fluoro-3-methyl-4-(piperidin-4-ylmethyl)-2-(trifluoromethyl)-1H-indole-7-carboxamide,TFA salt.

To a solution of5-fluoro-3-methyl-4-(piperidin-4-ylmethyl)-2-(trifluoromethyl)-1H-indole-7-carboxamide,TFA salt and TEA (0.023 mL, 0.165 mmol) in DMF (0.3 mL) and DCM (1.0 mL)was added a solution of acryloyl chloride (2.68 μl, 0.033 mmol) in DCM(0.3 mL), the mixture was stirred at room temperature for 30 min. Themixture was concentrated. The crude product was purified by prep-HPLC(PHENOMENEX®, Luna 5μ 30×250 mm, flow rate=30 ml/min., gradient=20% A to100% B in 30 min., A=H₂O/MeOH/TFA (90:10:0.1), B═H₂O/MeOH/TFA(10:90:0.1)). Yield4-((1-acryloylpiperidin-4-yl)methyl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide(3.8 mg, 8.78 μmol, 26.6% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.12 (br.s., 1H), 8.27 (br. s., 1H), 7.81 (d, J=10.9 Hz, 1H), 7.70 (br. s., 1H),6.79 (dd, J=16.7, 10.5 Hz, 1H), 6.08 (dd, J=16.7, 2.2 Hz, 1H), 5.65 (dd,J=10.5, 2.2 Hz, 1H), 4.40 (d, J=13.5 Hz, 1H), 4.02 (d, J=12.7 Hz, 1H),3.06-2.86 (m, 3H), 1.84 (br. s., 1H), 1.64 (d, J=12.5 Hz, 2H), 1.32-1.10(m, 3H). LCMS: 0.93 min., M+H 412.

Examples 231 and 232 (Atropisomers)4-(2-Acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

Intermediate 231A: Ethyl 2-(2-chloro-6-methylphenyl)-2,2-difluoroacetate

To a suspension of copper (1.057 g, 16.63 mmol) and1-chloro-2-iodo-3-methylbenzene (1.50 g, 5.94 mmol) in DMSO (5.0 mL) wasadded ethyl 2-bromo-2,2-difluoroacetate (1.206 g, 5.94 mmol), themixture was stirred at 55° C. for 18 hr. The mixture was poured into acold solution of saturated NH₄Cl in water (100 mL) and was extractedwith EtOAc (70 mL). The EtOAc was then washed with a solution of 1.0 Naqueous HCl (2×50 mL). The ethyl acetate layer was dried over sodiumsulfate and concentrated. The crude product was subjected to ISCO flashchromatography (silica gel/hexane-EtOAc 100:0 to 70:30 gradient). Yieldethyl 2-(2-chloro-6-methylphenyl)-2,2-difluoroacetate (1.26 g, 4.81mmol, 81% yield) as clear oil. ¹H NMR (400 MHz, chloroform-d) δ7.33-7.24 (m, 2H), 7.23-7.11 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 2.58 (t,J=5.9 Hz, 3H), 1.41-1.30 (m, 3H).

Intermediate 231B: Ethyl2-(2-(bromomethyl)-6-chlorophenyl)-2,2-difluoroacetate

A mixture of ethyl 2-(2-chloro-6-methylphenyl)-2,2-difluoroacetate (1.26g, 5.07 mmol), NBS (0.947 g, 5.32 mmol), and benzoyl peroxide (0.123 g,0.507 mmol) in CCl₄ (15 mL) was stirred at reflux for 4 hr. The mixturewas cooled to room temperature. The precipitate was filtered off and thefiltrate was concentrated. Crude yield ethyl2-(2-(bromomethyl)-6-chlorophenyl)-2,2-difluoroacetate (1.81 g, 4.42mmol, 87% yield) as light brown gum. ¹H NMR (400 MHz, chloroform-d) δ7.45-7.39 (m, 2H), 7.33-7.26 (m, 1H), 4.74 (t, J=2.1 Hz, 2H), 4.43-4.37(m, 2H), 1.37-1.33 (m, 3H).

Intermediate 231C: Ethyl2-(2-(azidomethyl)-6-chlorophenyl)-2,2-difluoroacetate

A mixture of ethyl2-(2-(bromomethyl)-6-chlorophenyl)-2,2-difluoroacetate (1.81 g, 5.53mmol) and sodium azide (0.718 g, 11.05 mmol) in DMF (15 mL) was stirredat room temperature for 18 hr. The mixture was diluted with EtOAc (35mL) and was washed with a solution of aqueous saturated sodiumbicarbonate (2×35 mL) and aqueous 1.0 M HCl (35 mL). The ethyl acetatelayer was dried over sodium sulfate and concentrated. The crude productwas subjected to ISCO flash chromatography (silica gel/hexane-EtOAc100:0 to 0:100 gradient). Yield ethyl2-(2-(azidomethyl)-6-chlorophenyl)-2,2-difluoroacetate (1.36 g, 4.46mmol, 81% yield) as clear gum. ¹H NMR (400 MHz, chloroform-d) δ7.51-7.41 (m, 3H), 4.69 (t, J=3.1 Hz, 2H), 4.44-4.34 (m, 2H), 1.39-1.30(m, 3H).

Intermediate 231D:5-Chloro-4,4-difluoro-1,2-dihydroisoquinolin-3(4H)-one

A mixture of ethyl2-(2-(azidomethyl)-6-chlorophenyl)-2,2-difluoroacetate (1.25 g, 4.32mmol) and platinum(IV) oxide (0.098 g, 0.432 mmol) in MeOH (10 mL) washydrogenated at 1 atm of hydrogen for 2 hr. Platinum was filtered offand the filtrate was concentrated. Yield5-chloro-4,4-difluoro-1,2-dihydroisoquinolin-3(4H)-one (950 mg, 4.15mmol, 96% yield) as white solid. ¹H NMR (400 MHz, methanol-d₄) δ7.59-7.52 (m, 2H), 7.35 (d, J=4.6 Hz, 1H), 4.70 (t, J=3.5 Hz, 2H).

Intermediate 231E: tert-Butyl5-chloro-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of 5-chloro-4,4-difluoro-1,2-dihydroisoquinolin-3(4H)-one(950 mg, 4.37 mmol) in THF (5.0 mL) was added 1.0M boranetetrahydrofuran complex in THF (24.01 mL, 24.01 mmol), the mixture wasstirred reflux for 2 hr. The mixture was cooled to room temperature andthe mixture was quenched with a solution of 1.0 M aqueous HCl (17.46 mL,17.46 mmol). The mixture was stirred at reflux for 2 hr and cooled toroom temperature. The mixture was concentrated. The mixture was washedwith ethyl ether (2×80 mL). A solution of aqueous 10 N NaOH was addeduntil pH 10 and was extracted with EtOAc (2×50 mL). The ethyl acetatelayer was dried over sodium sulfate and concentrated to give5-chloro-4,4-difluoro-1,2,3,4-tetrahydroisoquinoline.

To a solution of 5-chloro-4,4-difluoro-1,2,3,4-tetrahydroisoquinoline inTHF (15 mL) was added BOC₂O (1.014 mL, 4.37 mmol), the mixture wasstirred at room temperature for 60 min. The mixture was concentrated.The crude product was subjected to ISCO flash chromatography (silicagel/hexane-EtOAc 100:0 to 0:100 gradient). Yield tert-butyl5-chloro-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (960 mg,3.00 mmol, 68.8% yield) as clear gum. ¹H NMR (400 MHz, chloroform-d) δ7.36 (d, J=12.8 Hz, 2H), 7.17-7.07 (m, 1H), 4.68 (br. s., 2H), 4.06 (t,J=12.0 Hz, 2H), 1.51 (s, 9H).

Intermediate 231F: tert-Butyl4,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of bis(pinacolato) diboron (881 mg, 3.47 mmol), tert-butyl5-chloro-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (527 mg,1.735 mmol), potassium acetate (511 mg, 5.21 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (56.5 mg,0.087 mmol) in dioxane (6.0 mL) under nitrogen was stirred at 90° C. for18 hr. The mixture was diluted with EtOAc (15 mL) and was washed with asolution of aqueous saturated sodium bicarbonate (15 mL). The ethylacetate layer was dried over sodium sulfate and concentrated. The crudeproduct was subjected to ISCO flash chromatography (silicagel/hexane-EtOAc 100:0 to 70:30 gradient). Yield tert-butyl4,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(160 mg, 0.385 mmol, 22.16% yield) as light brown gum.

Intermediate 231G: tert-Butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of tert-butyl4,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(160 mg, 0.405 mmol),4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (115 mg, 0.405mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride(13.19 mg, 0.020 mmol) and potassium phosphate tribasic (258 mg, 1.214mmol) in THF (3.0 mL) and water (1.500 mL) was stirred at 50° C. in aseal vial under nitrogen for 4 hr. EtOAc (5.0 mL) was added to extractthe product. The EtOAc layer was dried over sodium sulfate andconcentrated. The crude product was subjected to ISCO flashchromatography (silica gel/hexane-10% MeOH/EtOAc 100:0 to 50:50gradient). Yield tert-butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(125 mg, 0.238 mmol, 58.7% yield) as light brown foam. Mass spectrum m/z474 (M+H)⁺.

Examples 231 and 232

A mixture of tert-butyl5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(125 mg, 0.264 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred atroom temperature for 30 min. The mixture was then concentrated to give4-(4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide.

To a solution of4-(4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamideand TEA (0.110 mL, 0.792 mmol) in DCM (3.0 mL) at 0° C. was added asolution of acryloyl chloride (23.89 mg, 0.264 mmol) in DCM (0.30 mL),the mixture was stirred at 0° C. for 30 min. The mixture was dilutedwith DCM (5 mL) and was washed with a solution of aqueous saturatedsodium bicarbonate (5 mL). The DCM layer was dried over sodium sulfateand concentrated. The crude product was subjected to ISCO flashchromatography (silica gel/hexane-10% MeOH/EtOAc 100:0 to 0:100gradient). Yield4-(2-acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide(76 mg, 0.169 mmol, 64.0% yield) as light brown gum.

4-(2-Acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamidewas separated by chiral super-critical fluid chromatography (CHIRALCEL®OJ (3×25 cm, 5 μm); mobile phase: 20% MeOH in CO₂ at 120 mL/min; 100bar, 30° C.; sample preparation: 76 mg in 7 mL MeOH. The first peakeluting from the column provided one enantiomer of4-(2-acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide[Intermediate 1] as a white powder (33 mg). The second peak eluting fromthe column provided the other enantiomer of4-(2-acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamideas a white powder (30 mg).

Additional Examples were prepared by procedures described above orsimilar procedures to those known in the art, using the appropriatestarting materials, are shown in Table 10.

TABLE 10 Ex. Starting Mass No. Structure Name Intermediate Spectrum 233

4-(1-acryloyl-1,4,5,6- tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H- indole-7-carboxamide 108 m/z 342 (M + H)⁺ 234

4-(1-acryloyl-2,5- dihydro-1H-pyrrol-3-yl)- 5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide 2 m/z 328 (M + H)⁺ 235

4-(1-acryloyl-2,5- dihydro-1H-pyrrol-2-yl)- 5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide 2 m/z 328 (M + H)⁺ 236

4-(1-acryloyl-1,2,3,6- tetrahydropyridin-4-yl)-5-fluoro-2,3-dimethyl-1H- indole-7-carboxamide 2 m/z 342 (M + H)⁺ 237

4-(1-acryloyl-2,5- dihydro-1H-pyrrol-3-yl)- 5-fluoro-3-methyl-2-(trifluoromethyl)-1H- indole-7-carboxamide 91 m/z 382 (M + H)⁺ 238

4-(1-(but-2-ynoyl)-2,5- dihydro-1H-pyrrol-3-yl)- 5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide 2 m/z 340 (M + H)⁺ 239

4-(2-acryloyl-1,2,3,4- tetrahydroisoquinolin-5- yl)-5-chloro-2,3-dimethyl-1H-indole-7- carboxamide, racemate 3 m/z 408, 410 (M + H)⁺ 240

4-(2-acryloyl-1,2,3,4- tetrahydroisoquinolin-5- yl)-5-chloro-2,3-dimethyl-1H-indole-7- carboxamide, atropisomer A 3 m/z 408, 410 (M + H)⁺241

4-(2-acryloyl-1,2,3,4- tetrahydroisoquinolin-5- yl)-2,3-dimethyl-1H-indole-7-carboxamide 1 m/z 374 (M + H)⁺ 242

(S)-5-fluoro-2,3- dimethyl-4-(3- propiolamidopiperidin-1-yl)-1H-indole-7- carboxamide 16 m/z 357 (M + H)⁺ 243

(R)-4-(3-(but-2- ynamido)piperidin-1-yl)- 5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide 12 m/z 371 (M + H)⁺ 244

4-(6-acryloyl-3,6- diazabicyclo[3.2.0] heptan-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7- carboxamide 12 m/z 357 (M + H)⁺ 245

4-(6-(but-2-ynoyl)-3,6- diazabicyclo[3.2.0] heptan-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7- carboxamide 12 m/z 369 (M + H)⁺ 246

4-(7-acryloyl-2,7- diazaspiro[4.4]nonan-2- yl)-5-fluoro-2,3-dimethyl-1H-indole-7- carboxamide 107 m/z 385 (M + H)⁺ 247

4-(7-(but-2-ynoyl)-2,7- diazaspiro[4.4]nonan-2- yl)-5-fluoro-2,3-dimethyl-1H-indole-7- carboxamide 107 m/z 397 (M + H)⁺ 248

5-fluoro-2,3-dimethyl-4- (2-vinylpyridin-3-yl)-1H- indole-7-carboxamide2 m/z 310 (M + H)⁺ 249

5-fluoro-3-methyl-2- (trifluoromethyl)-4-((6- vinylpyridin-3-yl)methyl)-1H-indole-7- carboxamide 91 m/z 378 (M + H)⁺ 250

4-(1-acryloylpyrrolidin-3- yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H- indole-7-carboxamide 91 m/z 384 (M + H)⁺ 251

4-(1-acryloylpyrrolidin-2- yl)-5-fluoro-2,3- dimethyl-1H-indole-7-carboxamide 2 m/z 330 (M + H)⁺ 252

4-(1-acryloylpyrrolidin-3- yl)-5-fluoro-2,3- dimethyl-1H-indole-7-carboxamide 2 m/z 330 (M + H)⁺ 253

5-fluoro-2,3-dimethyl-4- (3-vinyl-5,6- dihydroisoquinolin-8-yl)-1H-indole-7-carboxamide 2 m/z 362 (M + H)⁺ 254

4-(1-(but-2-ynoyl)-2,5- dihydro-1H-pyrrol-3-yl)- 5-fluoro-3-methyl-2-(trifluoromethyl)-1H- indole-7-carboxamide 109 m/z 394 (M + H)⁺ 255

4-(1-acryloyloctahydro- 6H-pyrrolo[3,4-b]pyridin-6-yl)-5-fluoro-3-methyl- 2-(trifluoromethyl)-1H- indole-7-carboxamide109 m/z 439 (M + H)⁺ 256

4-(1-(but-2-ynoyl) octahydro-6H-pyrrolo [3,4-b]pyridin-6-yl)-5-fluoro-3-methyl-2- (trifluoromethyl)-1H- indole-7-carboxamide 109 m/z451 (M + H)⁺

Additional Examples were prepared by procedures described above orsimilar procedures to those known in the art, using the appropriatestarting materials, are shown in Table 11.

TABLE 11 Ex. Mass No. Structure Name Spectrum 257

4-((1-acryloylpiperidin-4-ylidene) methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide m/z 356 (M + H)⁺ 258

4-((1-acryloylpiperidin-4- yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide m/z 358 (M + H)⁺ 259

4-((1-acryloylpyrrolidin-3- yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide m/z 344 (M + H)⁺ 260

4-((1-(but-2-ynoyl)piperidin-4- yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide m/z 370 (M + H)⁺ 261

4-((1-(but-2-ynoyl)piperidin-4- ylidene)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide m/z 368 (M + H)⁺ 262

4-((1-(but-2-ynoyl)pyrrolidin-3- yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide m/z 356 (M + H)⁺ 263

5-fluoro-4-(3-fluoro-2-vinylpyridin- 4-yl)-2,3-dimethyl-1H-indole-7-carboxamide m/z 328 (M + H)⁺ 264

4-(2-acryloyl-1,2,3,4- tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7- carboxamide, atropisomer B m/z 408 (M +H)⁺ 265

4-(2-(but-2-ynoyl)-1,2,3,4- tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7- carboxamide m/z 420 (M + H)⁺

Biological Assays

The pharmacological properties of the compounds of this invention may beconfirmed by a number of biological assays. The exemplified biologicalassays, which follow, have been carried out with compounds of theinvention.

Human Recombinant Btk Enzyme Assay

To V-bottom 384-well plates were added test compounds, human recombinantBtk (1 nM, Invitrogen Corporation), fluoresceinated peptide (1.5 μM),ATP (20 μM), and assay buffer (20 mM HEPES pH 7.4, 10 mM MgCl₂, 0.015%Brij 35 surfactant and 4 mM DTT in 1.6% DMSO), with a final volume of 30μL. After incubating at room temperature for 60 min., the reaction wasterminated by adding 45 μL of 35 mM EDTA to each sample. The reactionmixture was analyzed on the Caliper LABCHIP® 3000 (Caliper, Hopkinton,Mass.) by electrophoretic separation of the fluorescent substrate andphosphorylated product. Inhibition data were calculated by comparison tocontrol reactions with no enzyme (for 100% inhibition) and controls withno inhibitor (for 0% inhibition). Dose response curves were generated todetermine the concentration required for inhibiting 50% of Btk activity(IC₅₀). Compounds were dissolved at 10 mM in DMSO and evaluated ateleven concentrations.

Ramos FLIPR Assay

Ramos RA1 B cells (ATCC CRL-1596) at a density of 2×10⁶ cells/mL in RPMIminus phenol red (Invitrogen 11835-030) and 50 mM HEPES (Invitrogen15630-130) containing 0.1% BSA (Sigma A8577) were added to one halfvolume of calcium loading buffer (BD bulk kit for probenecid sensitiveassays, #640177) and incubated at room temperature in the dark for 1 hr.Dye-loaded cells were pelleted (Beckmann GS-CKR, 1200 rpm, roomtemperature, 5 min) and resuspended at room temperature in RPMI minusphenol red with 50 mM HEPES and 10% FBS to a density of 1×10⁶ cells/mL.150 μL aliquots (150,000 cells/well) were plated into 96 wellpoly-D-lysine coated assay plates (BD 35 4640) and briefly centrifuged(Beckmann GS-CKR 800 rpm, 5 min., without brake). Next, 50 μL compounddilutions in 0.4% DMSO/RPMI minus phenol red+50 mM HEPES+10% FBS wereadded to the wells and the plate was incubated at room temperature inthe dark for 1 hr. The assay plate was briefly centrifuged as aboveprior to measuring calcium levels. Using the FLIPR1 (Molecular Devices),cells were stimulated by adding goat anti-human IgM (Invitrogen AHI0601)to 2.5 μg/mL. Changes in intracellular calcium concentrations weremeasured for 180 seconds and percent inhibition was determined relativeto peak calcium levels seen in the presence of stimulation only.

Table 12 below lists the Btk and the Ramos IC₅₀ values for the followingExamples of this invention measured in the human recombinant Btk enzymeassay and the Ramos FLIPR assay. The compounds of the present invention,as exemplified by the following Examples, showed Btk IC₅₀ values of lessthan 700 nM.

TABLE 12 Example Btk IC₅₀ value (nM) Ramos IC₅₀ value (nM) 1 1.2 15 20.60 51 3 0.49 91 4 0.080 6.4 5 0.38 9.2 6 13 1300 7 0.31 34 8 15 9200 963 5300 10 120 6600 11 60 7600 12 510 11000 13 74 990 14 110 1300 15 52850 16 0.98 38 17 36 1000 18 16 750 19 130 5600 20 0.59 61 21 66 1000 220.21 16 23 0.11 26 24 0.14 11 25 0.070 63 26 0.50 35 27 0.33 39 28 0.2563 29 0.23 170 30 1.7 290 31 0.30 16 32 0.42 81 33 0.12 98 34 0.14 23 3517 380 36 49 4100 37 87 4300 38 0.66 42 39 16 30 40 0.25 66 41 5.0 58042 2.2 480 43 1.7 24 44 640 >300 45 1.1 57 46 3.3 450 47 29 500 48 14910 49 12 890 50 15 450 51 48 860 52 400 — 53 310 — 54 220 — 55 250 — 56390 — 57 300 — 58 170 — 59 92 >2000 60 81 >2000 61 120 >2000 62130 >2000 63 34  (35% @2000) 64 150 >2000 65 160 >2000 66 100  (26%@2000) 67 13 250 68 15 410 69 550 — 70 11 >300 71 74 900 72 19 1500 7392 1200 74 38 >2000 75 260 >2000 76 29  (22% @2000) 77 0.38 24 78 1.8 8179 3.3 43 80 1.1 54 81 20 310 82 4.2 270 83 3.3 100 84 53 320 85 9.9 36086 4.6 13 87 8.4 >300 88 3.3 5.2 89 1.0 29 90 12 130 91 59 >300 92 1.722 93 3.5 20 94 1.2 46 95 0.13 23 96 1.0 20 97 0.12 77 98 1.6 220 990.19 22 100 1.0 120 101 13 >300 102 0.17 14 103 2.4 9.4 104 33 (32%@300) 105 0.64 26 106 29 >300 107 260 >300 108 3.1 160 109 0.95 63 1100.39 3.9 111 8.8 (48% @300) 112 1.1 24 113 1.1 17 114 0.85 16 115 0.145.4 116 0.52 40 117 1.4 26 118 5.6 70 119 6.5 7.2 120 4.5 36 121 60 (33%@300) 122 84 >300 123 0.09 8.0 124 92 (30% @300) 125 0.14 9.8 126 0.062.8 127 0.17 24 128 0.06 10 129 14 (32% @300) 130 0.21 25 131 0.47 73132 0.15 28 133 71 >300 134 150 >300 135 0.30 27 136 0.050 5.8 13746 >300 138 0.93 65 139 1.2 30 140 3.5 170 141 0.72 18 142 2.7 — 143 1.228 144 1.0 22 145 0.29 8.2 146 0.20 5.0 147 3.0 46 148 22 (24% @300) 14960 (35% @300) 150 11 63 151 560 >300 152 76 (21% @300) 153 5.0 230 1540.10 4.7 155 0.15 0.20 156 3.1 3.1 157 620 — 158 49 — 159 0.09 3.7 1600.10 13 161 3.3 — 162 280 >300 163 720 >300 164 2.6 25% @300 165 0.17 90166 8.8 >300 167 0.37 58 168 0.04 3.3 169 61 >300 170 0.080 6.1 171 2.2150 172 0.74 17 173 0.66 130 174 0.09 74 175 110 >300 176 15 >300 1772.8 >300 178 1.9 290 179 92 >300 180 20 13% @300 181 0.40 51 1822.9 >300 183 0.29 26 184 3.5 110 185 0.13 12 186 0.80 20 187 40 >300 1880.60 5.1 189 0.16 21 190 38 >300 191 0.13 12 192 2.8 (23% @300) 193 0.1417 194 0.23 35 195 0.12 15 196 2.7 — 197 0.54 36 198 150 — 199 0.24 —200 0.27 34 201 260 (22% @300) 202 120 >300 203 31 — 204 0.33 — 20516 >300 206 0.040 57 207 0.094 — 208 0.32 6.5 209 0.24 73 210 6.4 >300211 0.20 41 212 0.50 40 213 0.29 51 214 29 >300 215 0.76 55 216 0.20 1.9217 0.19 11 218 5.8 (40% @300) 219 0.052 4.8 220 39 (28% @300) 22111 >300 222 2.6 >300 223 0.11 11 224 0.2 ND 225 0.6 53 226 0.4 84 2270.3 34 228 1181.4 ND 229 0.9 ND 230 51.4 ND 231 3.4 78 232 0.1 1 233 0.14 234 0.2 18 235 0.3 14 236 0.3     45% at 0.3 μM 237 0.9 81 238 3.5 0239 0.5 44 240 0.2 6 241 0.6 ND 242 0.1 ND 243 0.2 4 244 0.3 ND 245 0.737 246 0.4 ND 247 0.3 ND 248 3.6 ND 249 5.2 ND 250 8.5 ND 251 2.0 ND 2522.7 ND 253 2.7 277 254 35.6 ND 255 pending ND 256 pending ND 257 0.4 ND258 5.6 ND 259 2.3 40% Ramos at 0.3 μM 260 233.0 ND 261 46.9 ND 262 14.2ND 263 146.0 ND 264 43.2 ND

The compounds of the present invention possess activity as inhibitors ofBtk, and therefore, may be used in the treatment of diseases associatedwith Btk activity.

Collagen-Induced Arthritis in Mice:

DBA/1 male mice (8-10 wk of age; Harlan) were immunized subcutaneouslyat the base of the tail on Day 0 and again on Day 21 with 200 g bovinetype II collagen mixed with reconstituted Sigma Adjuvant System (SAS;Sigma-Aldrich). Daily oral (PO) dosing was immediately initiated withExample 223 or methotrexate (1 mg/kg) in PEG400:water (80:20) andcontinued to the end of the study (38 days).

Following the booster immunization, mice were monitored three times perweek for the development and severity of paw inflammation. Each paw wasvisually scored by the following scheme: +0=normal; +1=one (or more)joints inflamed on digits; +2=mild-moderate inflammation of plantarsurface of paw and paw thickness modestly increased; +3=moderate-severeinflammation of plantar surface of paw and paw thickness significantlyincreased; +4=ankylosis of ankle joint (significantly reduced jointmotion on flexion/extension). Clinical paw scores for all four paws weresummed for each mouse, and the mean was calculated for each treatmentgroup.

Results:

Treatment with Example 223 provided dose-responsive inhibition ofclinically evident disease, with 21%, 83%, and 93% inhibition of meanclinical scores at the end of the study at doses of 0.1, 0.5, and 2.5mg/kg orally QD, respectively. In contrast, treatment with methotrexateat 1 mg/kg, the standard of care in rheumatoid arthritis, showed only58% inhibition of clinical scores.

NZB/W Lupus-Prone Mice:

Female NZB/WF1 mice, age 24 weeks were dosed by oral gavage, once daily,for 16 weeks and included the following treatment groups: Example 223 at0.2, 0.5 and 1.5 mg/kg in vehicle (80:20 PEG400:water), vehicle alone,or prednisolone at 10 mg/kg. Proteinuria was measured using acolorimetric assay for albumin (Siemens Albustix Reagent Strips forUrinalysis).

At the end of the study, kidneys were collected in 10% Neutral BufferedFormalin for histological evaluation. Fixed kidney tissues wereroutinely processed and paraffin embedded. Kidney sections were stainedwith periodic acid Schiff and hematoxylin (PASH) and hematoxylin andeosin (H&E) for the evaluation of nephritis severity. Blinded totreatment group, severity of nephritis was evaluated using the followingcriteria. For glomerular damage: 1-Mesangial matrix thickening and/ormesangial cell proliferation; 2—Crescent formation—Cellulardeposits/casts in Bowman's space; 3-Cellular infiltration—composed ofmononuclear cells in glomerular tufts; 4—Fibrosis of Bowman's capsule.For tubular damage: 1—Infiltration of mononuclear cells; 2—Severity oftubular epithelial cell damage; 3-Protein casts. For tubulo-interstitialdamage: 1-Fibrosis; 2—Infiltration of mononuclear cells. Eachsubcategory was assigned a score from 0 to 4. The total score for eachmouse was the sum of the above 9 subcategories.

Results:

Treatment with Example 223 showed dose dependent inhibition of severeproteinuria, a measure of the underlying nephritis, at the end of thestudy, with 42%, 17%, and 8% of the mice showing severe proteinuria(≥300 mg/dL) at doses of 0.2, 0.5 and 1.5 mg/kg, respectively. Incomparison, 75% of the vehicle control animals showed severeproteinuria. Histological evaluation of the kidneys from vehicle controlmice showed advanced nephritis, with mesangial hypertrophy of theglomeruli, prominent cellular casts/crescents and capsular fibrosis.Tubular epithelial cells were frequently damaged and protein casts werenumerous. In addition, there was a prominent mononuclear cell infiltratepresent in the interstitium of many of the kidneys examined. The resultsof the present study show that the Total Nephritis Histology SeverigyScores for the three groups of mice treated with 0.2, 0.5 and 1.5 mg/kgof Example 223 were 6.4, 7.5, and 5.0, respectively. In comparison, thegroups of mice treated with either prednisolone or vehicle only hadTotal Nephritis Histology Severigy Scores of 7.8 and 21.0, respectively.In summary, the results of the present study indicates that treatmentwith Example 223 at all doses provided protection againsttubulo-interstitial and glomerular nephritis as well as inflammatoryinfiltration.

TABLE 13 Effect of Example 223 on Nephritis in NZB/W Lupus-Prone MiceGlomerular Tubulo-Interstitial Total Nephritis Nephritis NephritisHistology Severity Score Severity Score Severity Score Treatment (GroupMean) (Group Mean) (Group Mean) None (Vehicle) 9.0 12.0 21.0 0.2 mg/kg2.4 4.0 6.4 Example 223 0.5 mg/kg 3.7 3.8 7.5 Example 223 1.5 mg/kg 2.22.8 5.0 Example 223  10 mg/kg 4.5 3.3 7.8 Prednisolone

1-17. (canceled)
 18. A compound of Formula (I):

wherein: X is CR₄; A is

Q₂ is —CN, —C(O)(C₁₋₄ alkyl substituted with zero or 1 R₁₁), —C(O)(C₃₋₆cycloalkyl substituted with zero or 1 R₁₁), —C(O)(C₅₋₆ cycloalkenyl),—C(O)CR₁₀═CR₁₀R₁₀, —C(O)C(R₁₀)═CHCH₂N(CH₃)₂, —C(O)C≡CR₇, —C(O)C≡C(C₁₋₃hydroxyalkyl), —C(O)C≡C(phenyl), —C(O)C≡CSi(CH₃)₃, or —S(O)₂CH═CHR₁₀; R₁is H, —CH₃, —CF₃, or phenyl substituted with zero or 1 R₁₂; R₂ is H,—CH₃, cyclopropyl, or phenyl substituted with zero or 1 R₁₂, providedthat zero or one of R₁ and R₂ is phenyl substituted with zero or 1 R₁₂;R₃ is F, Cl, or I; R₄ is H, F, —OH, or —OCH₃; each R₇ is H, C₁₋₄ alkyl,or cyclopropyl; R₁₀, at each occurrence, is independently H or —CH₃; Ruis F, Cl, —CN, —CF₃, or C₁₋₃ alkoxy; and R₁₂ is F, Cl, —CN, —CF₃, orC₁₋₃ alkoxy.
 19. The compound according to claim 18 wherein: R₁ is H or—CH₃; R₂ is H or —CH₃; R₃ is F or Cl; and R₄ is H or F.
 20. The compoundaccording to claim 18 wherein R₃ is F.
 21. The compound according toclaim 18 wherein: R₁ is —CH₃; R₂ is —CH₃; R₃ is H or F; R₄ is H; andeach R₇ is H or —CH₃.
 22. The compound according to claim 18 wherein: Q₂is —CN, —C(O)CH═CH₂, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)C≡CH, —C(O)C≡C(CH₃), or—S(O)₂CH═CH₂.
 23. The compound according to claim 18 having thestructure:


24. A pharmaceutical composition comprising a compound according toclaim 18 or a pharmaceutically-acceptable salt thereof; and apharmaceutically acceptable carrier.
 25. A method for treating a diseasecomprising the administration to a subject in need thereof atherapeutically-effective amount of at least one compound according toclaim 18 or a pharmaceutically-acceptable salt thereof, wherein saiddisease is selected from systemic lupus erythematosus (SLE), rheumatoidarthritis, multiple sclerosis (MS), and Sjögren's syndrome.